109 results on '"Dirk Schubert"'
Search Results
2. A humanin vitroneuronal model for studying homeostatic plasticity at the network level
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Xiuming Yuan, Sofía Puvogel, Jon-Ruben van Rhijn, Anna Esteve-Codina, Mandy Meijer, Simon Rouschop, Eline J.H. van Hugte, Astrid Oudakker, Chantal Schoenmaker, Dirk Schubert, Barbara Franke, and Nael Nadif Kasri
- Abstract
SummaryMechanisms that underlie homeostatic plasticity have been extensively investigated at single-cell levels in animal models, but are less well understood at the network level. Here, we used microelectrode arrays to characterize neuronal networks following induction of homeostatic plasticity in human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons co-cultured with rat astrocytes. Chronic suppression of neuronal activity through tetrodotoxin (TTX) elicited a time-dependent network re-arrangement. Increased expression of AMPA receptors and the elongation of axon initial segments were associated with increased network excitability following TTX treatment. Transcriptomic profiling of TTX-treated neurons revealed up-regulated genes related to extracellular matrix organization, while down-regulated genes related to cell communication; also astrocytic gene expression was found altered. Overall, our study shows that hiPSC-derived neuronal networks provide a reliablein vitroplatform to measure and characterize homeostatic plasticity at network and single-cell level; this platform can be extended to investigate altered homeostatic plasticity in brain disorders.
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- 2023
3. Cadherin-13 is a critical regulator of GABAergic modulation in human stem-cell-derived neuronal networks
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Teun M. Klein Gunnewiek, Maria Rosaria Vitale, Brooke L. Latour, Sophie Jansen, Nael Nadif Kasri, Jon-Ruben van Rhijn, Dirk Schubert, Eline J.H. van Hugte, Martijn Selten, Jitske Bak, Anouk H.A. Verboven, Alessia Anania, Ilse M. van der Werf, Katrin Linda, Klaus-Peter Lesch, Johanna E. M. Zöller, Hans van Bokhoven, Chantal Schoenmaker, Moritz Negwer, Britt Mossink, Monica Frega, Jason M. Keller, Shan Wang, Astrid R. Oudakker, Clinical Neurophysiology, TechMed Centre, Psychiatrie & Neuropsychologie, and RS: MHeNs - R3 - Neuroscience
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INTERNEURONS ,0301 basic medicine ,Integrins ,Induced Pluripotent Stem Cells ,Population ,INHIBITION ,Regulator ,ADHESION ,Inhibitory postsynaptic potential ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Glutamatergic ,0302 clinical medicine ,Humans ,TRANSCRIPTION FACTOR ,GABAergic Neurons ,GENOME-WIDE ASSOCIATION ,FUNCTIONAL MATURATION ,AUTISM ,Induced pluripotent stem cell ,education ,Molecular Biology ,education.field_of_study ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,RECEPTOR ,biology ,IMBALANCE ,Cadherins ,Psychiatry and Mental health ,Parvalbumins ,Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] ,030104 developmental biology ,Synapses ,T-CADHERIN ,biology.protein ,GABAergic ,Stem cell ,Neuroscience ,030217 neurology & neurosurgery ,Parvalbumin - Abstract
Activity in the healthy brain relies on a concerted interplay of excitation (E) and inhibition (I) via balanced synaptic communication between glutamatergic and GABAergic neurons. A growing number of studies imply that disruption of this E/I balance is a commonality in many brain disorders; however, obtaining mechanistic insight into these disruptions, with translational value for the patient, has typically been hampered by methodological limitations. Cadherin-13 (CDH13) has been associated with autism and attention-deficit/hyperactivity disorder. CDH13 localizes at inhibitory presynapses, specifically of parvalbumin (PV) and somatostatin (SST) expressing GABAergic neurons. However, the mechanism by which CDH13 regulates the function of inhibitory synapses in human neurons remains unknown. Starting from human-induced pluripotent stem cells, we established a robust method to generate a homogenous population of SST and MEF2C (PV-precursor marker protein) expressing GABAergic neurons (iGABA) in vitro, and co-cultured these with glutamatergic neurons at defined E/I ratios on micro-electrode arrays. We identified functional network parameters that are most reliably affected by GABAergic modulation as such, and through alterations of E/I balance by reduced expression of CDH13 in iGABAs. We found that CDH13 deficiency in iGABAs decreased E/I balance by means of increased inhibition. Moreover, CDH13 interacts with Integrin-β1 and Integrin-β3, which play opposite roles in the regulation of inhibitory synaptic strength via this interaction. Taken together, this model allows for standardized investigation of the E/I balance in a human neuronal background and can be deployed to dissect the cell-type-specific contribution of disease genes to the E/I balance.
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- 2022
4. SCN1A-deficient hiPSC-derived excitatory neuronal networks display mutation-specific phenotypes
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Eline J.H. van Hugte, Elly I. Lewerissa, Ka Man Wu, Giulia Parodi, Torben van Voorst, Naoki Kogo, Jason M. Keller, Dirk Schubert, Helenius J. Schelhaas, Judith Verhoeven, Marian Majoie, Hans van Bokhoven, and Nael Nadif Kasri
- Abstract
Dravet syndrome is a severe epileptic encephalopathy, characterized by (febrile) seizures, behavioral problems and developmental delay. 80% of Dravet syndrome patients have a mutation inSCN1A, encoding NaV1.1. Milder clinical phenotypes, such as GEFS+(generalized epilepsy with febrile seizures plus), can also arise fromSCN1Amutations. Predicting the clinical phenotypic outcome based on the type of mutation remains challenging, even when the same mutation is inherited within one family. Both this clinical and genetic heterogeneity add to the difficulties of predicting disease progression and tailored prescription of anti-seizure medication. A better understanding of the neuropathology of differentSCN1Amutations, might give insight in differentiating the expected clinical phenotype and best fit treatment choice. Initially it was recognized that loss of Na+-current in inhibitory neurons specifically resulted in disinhibition and consequently seizure generation. However, the extent to which excitatory neurons contribute to the pathophysiology is currently debated, and might depend on the patient clinical phenotype or the specific mutation inSCN1A.To examine the genotype-phenotype correlations ofSCN1Amutations in relation to excitatory neurons, we investigated a panel of patient-derived excitatory neuronal networks differentiated on multi-electrode arrays. We included patients with different clinical phenotypes, harboring different mutations inSCN1A, plus a family where the same mutation leads to both GEFS+ and Dravet syndrome.We hitherto describe a previously unidentified functional excitatory neuronal network phenotype in the context of epilepsy, which corresponded to seizurogenic network prediction patterns elicited by proconvulsive compounds. We find that excitatory neuronal networks were differently affected, dependent on the type of SCN1Amutation, but not on clinical severity. Specifically, pore domain mutations could be distinguished from voltage sensing domain mutations. Furthermore, all patients showed aggravated neuronal network responses upon febrile temperatures. While the basal neuronal network phenotypes could not be distinguished based on patient clinical severity, retrospective drug screening revealed that anti-seizure medication only affected GEFS+ patient-, but not Dravet patient-derived neuronal networks in a patient specific and clinically relevant manner. In conclusion, our results indicate a mutation-specific excitatory neuronal network phenotype, which recapitulates the foremost clinically relevant features, providing future opportunities for precision therapies.HighlightsHuman stem cell derived excitatory neurons are affected by mutations inSCN1Aand display mutation-specific, but not clinical phenotype specific, neuronal network phenotypesThe neuronal network phenotype we describe corresponds to seizurogenic network prediction patterns in vitroExcitatory neuronal networks respond to Dravet syndrome clinically relevant triggers, like febrile temperatures and Dravet-contraindicated ASM CarbamazepineRetrospective drug screening revealed that GEFS+ neuronal networks, but not Dravet neuronal networks respond to ASM in a patient-specific and clinical relevant manner
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- 2023
5. FriendlyClearMap: an optimized toolkit for mouse brain mapping and analysis
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Moritz Negwer, Bram Bosch, Maren Bormann, Rick Hesen, Lukas Lütje, Lynn Aarts, Carleen Rossing, Nael Nadif Kasri, and Dirk Schubert
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Health Informatics ,Computer Science Applications - Abstract
Background Tissue clearing is currently revolutionizing neuroanatomy by enabling organ-level imaging with cellular resolution. However, currently available tools for data analysis require a significant time investment for training and adaptation to each laboratory’s use case, which limits productivity. Here, we present FriendlyClearMap, an integrated toolset that makes ClearMap1 and ClearMap2’s CellMap pipeline easier to use, extends its functions, and provides Docker Images from which it can be run with minimal time investment. We also provide detailed tutorials for each step of the pipeline. Findings For more precise alignment, we add a landmark-based atlas registration to ClearMap’s functions as well as include young mouse reference atlases for developmental studies. We provide an alternative cell segmentation method besides ClearMap’s threshold-based approach: Ilastik’s Pixel Classification, importing segmentations from commercial image analysis packages and even manual annotations. Finally, we integrate BrainRender, a recently released visualization tool for advanced 3-dimensional visualization of the annotated cells. Conclusions As a proof of principle, we use FriendlyClearMap to quantify the distribution of the 3 main GABAergic interneuron subclasses (parvalbumin+ [PV+], somatostatin+, and vasoactive intestinal peptide+) in the mouse forebrain and midbrain. For PV+ neurons, we provide an additional dataset with adolescent vs. adult PV+ neuron density, showcasing the use for developmental studies. When combined with the analysis pipeline outlined above, our toolkit improves on the state-of-the-art packages by extending their function and making them easier to deploy at scale.
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- 2022
6. Human neuronal networks on micro-electrode arrays are a highly robust tool to study disease-specific genotype-phenotype correlations in vitro
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Giulia Parodi, Teun M. Klein Gunnewiek, Nael Nadif Kasri, Tjitske Kleefstra, Monica Frega, Hans van Bokhoven, Anouk H.A. Verboven, Katrin Linda, Dirk Schubert, Tamas Kozicz, Chantal Schoenmaker, Eline J.H. van Hugte, B. Mossink, Clinical Neurophysiology, and TechMed Centre
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Disease specific ,neuronal network activity ,UT-Gold-D ,Computer science ,Cell Culture Techniques ,Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13] ,Action Potentials ,Biology ,Biochemistry ,Article ,Mice ,Lab-On-A-Chip Devices ,Micro electrode ,Genetics ,Biological neural network ,Animals ,Humans ,Premovement neuronal activity ,Induced pluripotent stem cell ,Electrodes ,neuronal differentiation ,Genotype-Phenotype Correlations ,Cells, Cultured ,Genetic Association Studies ,Neurons ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Drug discovery ,food and beverages ,Robustness (evolution) ,Cell Differentiation ,Cell Biology ,Microarray Analysis ,Phenotype ,human induced pluripotent stem cells ,micro-electrode arrays ,Nerve Net ,Neuroscience ,Developmental Biology - Abstract
Summary Micro-electrode arrays (MEAs) are increasingly used to characterize neuronal network activity of human induced pluripotent stem cell (hiPSC)-derived neurons. Despite their gain in popularity, MEA recordings from hiPSC-derived neuronal networks are not always used to their full potential in respect to experimental design, execution, and data analysis. Therefore, we benchmarked the robustness of MEA-derived neuronal activity patterns from ten healthy individual control lines, and uncover comparable network phenotypes. To achieve standardization, we provide recommendations on experimental design and analysis. With such standardization, MEAs can be used as a reliable platform to distinguish (disease-specific) network phenotypes. In conclusion, we show that MEAs are a powerful and robust tool to uncover functional neuronal network phenotypes from hiPSC-derived neuronal networks, and provide an important resource to advance the hiPSC field toward the use of MEAs for disease phenotyping and drug discovery., Highlights • MEAs are a robust tool to model neuronal network functioning • Neuronal networks from different healthy donors show comparable network activity • MEAs are able to distinguish disease-specific neuronal network phenotypes • We provide recommendations to standardize neuronal network recordings on MEA, In this article, Mossink and colleagues demonstrate that micro-electrode arrays (MEAs) are a highly robust tool to uncover genotype/phenotype interactions in hiPSC-derived excitatory neuronal networks, and provide an important resource for the design, execution, and analysis of hiPSC-derived neuronal networks studies on MEA.
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- 2021
7. Urban Hygiene and Slum Clearance as Catalysts
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Dirk Schubert
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- 2022
8. Generation of glutamatergic/GABAergic neuronal co-cultures derived from human induced pluripotent stem cells for characterizing E/I balance in vitro
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Shan Wang, Rick Hesen, Britt Mossink, Nael Nadif Kasri, and Dirk Schubert
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General Immunology and Microbiology ,General Neuroscience ,General Biochemistry, Genetics and Molecular Biology - Published
- 2023
9. Resilience and Path Dependence: A Comparative Study of the Port Cities of London, Hamburg, and Philadelphia
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Dirk Schubert and Carola Hein
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Philadelphia ,History ,Sociology and Political Science ,Corporate governance ,historical institutionalism ,06 humanities and the arts ,Public administration ,port cities ,Investment (macroeconomics) ,Port (computer networking) ,path dependence ,060104 history ,Urban Studies ,Resilience (organizational) ,Navy ,Hamburg ,Political science ,London ,0601 history and archaeology ,Historical institutionalism ,resilience ,Path dependence - Abstract
Port spaces, functions, and interests have shaped the growth and development of many cities around the world. At times, different stakeholders—private and public, local, regional, national and global—have collaborated to assure the continuity of port functions in old and new locations and, if the port relocates or if that effort fails, to redevelop former port spaces. Through the lens of port- and city-related urban developments in London, Hamburg, and Philadelphia, this article explores the multiple conditions that are part of port city resilience. It uses historical institutionalism as a theoretical framework for understanding these long-term changes, particularly in institutional and governance dynamics. It shows that the development paths of port and city spaces and the actors who shape them are not always aligned. Through the case of London, it shows a development path that is led by private investment building and relocating a world-class port and administrating it from the city center, while local and national institutions only intervene to balance spatial or social short-comings of the private actors. The case of the city-state Hamburg illustrates the development of shared port-city paths under long-term public leadership that has provided direction for the expanding port as well as for the growing city. In the case of Philadelphia, national interests, the Navy, and private investments played an important role in the creation of port infrastructure and, later, in the largely failed transformation of former port areas into public waterfronts. As shipping elites left the city and new land-based employers emerged, such as the University of Pennsylvania, the port-city path was partly discontinued. The article concludes by pointing to the expected capacity of each of these cities to address future challenges. Awareness of historical practices can help readers understand where current conditions may stand in the way of innovative solutions.
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- 2020
10. Fritz Schumacher – Neglected German town planner and urban reformer in Hamburg and Cologne
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Dirk Schubert
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German ,media_common.quotation_subject ,Geography, Planning and Development ,language ,Art history ,Art ,Town planner ,language.human_language ,media_common - Abstract
Fritz Schumacher (1869-1947), German town planner and reformer, is often mentioned as a ‘conservative modernist’ or as an ‘unmodern architect’ and neglected in the works on the origins of modern ho...
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- 2020
11. Paths to the Green City: On the Work of Fritz Schumacher
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Dirk Schubert
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- 2022
12. Repeated testing modulates chronic unpredictable mild stress effects in male rats
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Kari Bosch, Giulia Sbrini, Irene Burattini, Desirée Nieuwenhuis, Francesca Calabrese, Dirk Schubert, Marloes J.A.G. Henckens, and Judith R. Homberg
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Male ,Sucrose ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Depression ,Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13] ,Anxiety ,Stress ,Hippocampus ,Repeated testing ,Circadian Rhythm ,Rats ,CUMS ,Behavioral Neuroscience ,Disease Models, Animal ,Long-term ,Settore BIO/14 - Farmacologia ,Animals ,Humans ,Stress, Psychological - Abstract
Contains fulltext : 251390.pdf (Publisher’s version ) (Open Access) Depression is a highly prevalent, debilitating mental disorder. Chronic unpredictable mild stress (CUMS) is the most widely applied model to study this affliction in rodents. While studies incorporating CUMS prior to an intervention often require long-lasting stress effects that persist after exposure is ceased, the longevity of these effects is rarely studied. Additionally, it is unclear whether behavioural assessments can be performed before and after interventions without repeated testing effects. In rats, we investigated CUMS effects on components of depressive-like behaviour both acutely after stress cessation and after a recovery period, as well as effects of repeated testing. We observed acute disruptions of the circadian locomotor rhythm and a reduced sucrose preference immediately after CUMS exposure. While circadian locomotor rhythm effects persisted up until four weeks after stress cessation, independently of repeated testing, sucrose preference effects did not. Interestingly, CUMS animals tested once after a recovery period of four weeks showed reduced anxiety-like behaviour in the open field and elevated plus maze compared to their control group and repeatedly-tested CUMS animals. These findings suggest that distinct CUMS-induced components of depressive-like behaviour are affected differentially by recovery time and repeated testing; these aspects should be considered carefully in future study designs.
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- 2022
13. Imbalanced autophagy causes synaptic deficits in a human model for neurodevelopmental disorders
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Marina P Hommersom, Chantal Schoenmaker, Astrid R. Oudakker, Katrin Linda, Lynn Devilee, Elly Lewerissa, Nael Nadif Kasri, Anouk H.A. Verboven, Bert B.A. de Vries, Michele Gabriele, Giuseppe Testa, David A. Koolen, Hans van Bokhoven, Monica Frega, Teun M. Klein Gunnewiek, Edda Ulferts, Dirk Schubert, Clinical Neurophysiology, and TechMed Centre
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Autophagosome ,iPSCs ,Chromatin remodeling ,Epigenesis, Genetic ,Superoxide Dismutase-1 ,Sequestosome 1 ,Koolen-de Vries syndrome ,Intellectual Disability ,Lysosome ,medicine ,Autophagy ,neuronal development ,Humans ,Abnormalities, Multiple ,education ,synaptic function ,Molecular Biology ,Mechanistic target of rapamycin ,PI3K/AKT/mTOR pathway ,Sirolimus ,chemistry.chemical_classification ,reactive oxygen species ,Reactive oxygen species ,education.field_of_study ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,biology ,Lysine ,TOR Serine-Threonine Kinases ,MTOR ,Autophagosomes ,Cell Biology ,Cell biology ,medicine.anatomical_structure ,chemistry ,biology.protein ,Chromosome Deletion ,Lysosomes ,Chromosomes, Human, Pair 17 - Abstract
Contains fulltext : 248864.pdf (Publisher’s version ) (Open Access) Macroautophagy (hereafter referred to as autophagy) is a finely tuned process of programmed degradation and recycling of proteins and cellular components, which is crucial in neuronal function and synaptic integrity. Mounting evidence implicates chromatin remodeling in fine-tuning autophagy pathways. However, this epigenetic regulation is poorly understood in neurons. Here, we investigate the role in autophagy of KANSL1, a member of the nonspecific lethal complex, which acetylates histone H4 on lysine 16 (H4K16ac) to facilitate transcriptional activation. Loss-of-function of KANSL1 is strongly associated with the neurodevelopmental disorder Koolen-de Vries Syndrome (KdVS). Starting from KANSL1-deficient human induced-pluripotent stem cells, both from KdVS patients and genome-edited lines, we identified SOD1 (superoxide dismutase 1), an antioxidant enzyme, to be significantly decreased, leading to a subsequent increase in oxidative stress and autophagosome accumulation. In KANSL1-deficient neurons, autophagosome accumulation at excitatory synapses resulted in reduced synaptic density, reduced GRIA/AMPA receptor-mediated transmission and impaired neuronal network activity. Furthermore, we found that increased oxidative stress-mediated autophagosome accumulation leads to increased MTOR activation and decreased lysosome function, further preventing the clearing of autophagosomes. Finally, by pharmacologically reducing oxidative stress, we could rescue the aberrant autophagosome formation as well as synaptic and neuronal network activity in KANSL1-deficient neurons. Our findings thus point toward an important relation between oxidative stress-induced autophagy and synapse function, and demonstrate the importance of H4K16ac-mediated changes in chromatin structure to balance reactive oxygen species- and MTOR-dependent autophagy.Abbreviations: APO: apocynin; ATG: autophagy related; BAF: bafilomycin A(1); BSO: buthionine sulfoximine; CV: coefficient of variation; DIV: days in vitro; H4K16ac: histone 4 lysine 16 acetylation; iPSC: induced-pluripotent stem cell; KANSL1: KAT8 regulatory NSL complex subunit 1; KdVS: Koolen-de Vries Syndrome; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MEA: micro-electrode array; MTOR: mechanistic target of rapamycin kinase; NSL complex: nonspecific lethal complex; 8-oxo-dG: 8-hydroxydesoxyguanosine; RAP: rapamycin; ROS: reactive oxygen species; sEPSCs: spontaneous excitatory postsynaptic currents; SOD1: superoxide dismutase 1; SQSTM1/p62: sequestosome 1; SYN: synapsin; WRT: wortmannin.
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- 2022
14. Städtebau unter Salazar. Diktatorische Modernisierung des portugiesischen Imperiums 1926–1960
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Dirk Schubert
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Power (social and political) ,Legitimation ,Political science ,Geography, Planning and Development ,Economic history ,humanities - Abstract
This impressive book examines the legitimation of power, the production of consent, the demonstration of strength, effectiveness and speed in a country on the European periphery that has received l...
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- 2020
15. Manuale zum Städtebau. Die Systematisierung des Wissens von der Stadt 1870–1950
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Dirk Schubert
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media_common.quotation_subject ,Geography, Planning and Development ,Art ,Humanities ,Town planning ,media_common - Abstract
The book with the unwieldy title ‘Town Planning Manuals – The systematisation of knowledge on cities 1870–1950’ is a manual about manuals of town planning with far-reaching aspirations and a subjec...
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- 2020
16. Jane Jacobs, cities, urban planning, ethics and value systems
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Dirk Schubert
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Sociology and Political Science ,media_common.quotation_subject ,05 social sciences ,0211 other engineering and technologies ,0507 social and economic geography ,021107 urban & regional planning ,Environmental ethics ,Value system ,02 engineering and technology ,Development ,Value systems ,Urban Studies ,Urban planning ,Tourism, Leisure and Hospitality Management ,Paradigm shift ,Demolition ,Criticism ,Ideology ,Sociology ,050703 geography ,media_common - Abstract
This article deals with the philosophical and ethical background of Jane Jacobs's ideas on cities as organized complexity and her criticism of urban planning and urban renewal in the form of demolition and area remediation. Many publications have already examined her influence on development projects in as far as this is verifiable. Her contribution to the paradigm shift in urban planning has been reflected in many ways. However, her - not explicitly elaborated - ideological value system that runs through her publications and determined her actual conduct, still remains a desideratum of research.
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- 2019
17. Entangled Urbanisms
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Dirk Schubert
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Urban Studies ,History ,Sociology and Political Science - Published
- 2019
18. Glucocorticoid enhancement of recognition memory via basolateral amygdala-driven facilitation of prelimbic cortex interactions
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Giacomo Ronzoni, Daan van Kuppeveld, Qi Song, Dirk Schubert, Chunan Guo, Areg Barsegyan, James L. McGaugh, Selina Teurlings, Gabriele Mirone, Evelien H.S. Schut, Piray Atsak, and Benno Roozendaal
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Male ,Agonist ,medicine.drug_class ,Infralimbic cortex ,Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13] ,Insular cortex ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,All institutes and research themes of the Radboud University Medical Center ,Receptors, Glucocorticoid ,0302 clinical medicine ,Memory ,medicine ,Animals ,Premovement neuronal activity ,Androstanols ,Glucocorticoids ,030304 developmental biology ,Recognition memory ,Cerebral Cortex ,0303 health sciences ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Multidisciplinary ,Basolateral Nuclear Complex ,Biological Sciences ,Rats ,medicine.anatomical_structure ,RU-28362 ,chemistry ,Memory consolidation ,Nerve Net ,Neuroscience ,030217 neurology & neurosurgery ,Basolateral amygdala - Abstract
Extensive evidence indicates that the basolateral amygdala (BLA) interacts with other brain regions in mediating stress hormone and emotional arousal effects on memory consolidation. Brain activation studies have shown that arousing conditions lead to the activation of large-scale neural networks and several functional connections between brain regions beyond the BLA. Whether such distal interactions on memory consolidation also depend on BLA activity is not as yet known. We investigated, in male Sprague-Dawley rats, whether BLA activity enables prelimbic cortex (PrL) interactions with the anterior insular cortex (aIC) and dorsal hippocampus (dHPC) in regulating glucocorticoid effects on different components of object recognition memory. The glucocorticoid receptor (GR) agonist RU 28362 administered into the PrL, but not infralimbic cortex, immediately after object recognition training enhanced 24-hour memory of both the identity and location of the object via functional interactions with the aIC and dHPC, respectively. Importantly, posttraining inactivation of the BLA by the noradrenergic antagonist propranolol abolished the effect of GR agonist administration into the PrL on memory enhancement of both the identity and location of the object. BLA inactivation by propranolol also blocked the effect of GR agonist administration into the PrL on inducing changes in neuronal activity within the aIC and dHPC during the postlearning consolidation period as well as on structural changes in spine morphology assessed 24 hours later. These findings provide evidence that BLA noradrenergic activity enables functional interactions between the PrL and the aIC and dHPC in regulating stress hormone and emotional arousal effects on memory.
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- 2019
19. Cities and plans – the past defines the future
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Dirk Schubert
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060104 history ,Urban planning ,Geography, Planning and Development ,0211 other engineering and technologies ,021107 urban & regional planning ,0601 history and archaeology ,06 humanities and the arts ,02 engineering and technology ,Business ,Environmental planning ,Spatial allocation - Abstract
Urban planning is often considered unnecessary from a neo-liberal viewpoint, particularly as the market would guarantee an optimal spatial allocation of facilities and uses without it. Planning cos...
- Published
- 2018
20. Loss-of-Function Variants in the Schizophrenia Risk Gene Setd1a Alter Neuronal Network Activity in Human Neurons Through Camp/Pka Pathway
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Shan Wang, Jon-Ruben van Rhijn, Ibrahim Akkouh, Naoki Kogo, Nadine Maas, Anna Bleeck, Irene Santisteban Ortiz, Elly Lewerissa, Ka Man Wu, Chantal Schoenmaker, Srdjan Djurovic, Hans van Bokhoven, Tjitske Kleefstra, Nael Nadif Kasri, and Dirk Schubert
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History ,Polymers and Plastics ,Business and International Management ,Industrial and Manufacturing Engineering - Abstract
SummaryHeterozygous loss-of-function (LoF) mutations in SETD1A, which encodes a subunit of histone H3 lysine 4 methyltransferase, were shown to cause a novel neurodevelopmental syndrome and increase the risk for schizophrenia. We generated excitatory/inhibitory neuronal networks from human induced pluripotent stem cells with a SETD1A heterozygous LoF mutation (SETD1A+/-) using CRISPR/Cas9. Our data show that SETD1A haploinsufficiency resulted in morphologically increased dendritic complexity and functionally increased bursting activity. This network phenotype was primarily driven by SETD1A haploinsufficiency in glutamatergic neurons. In accordance with the functional changes, transcriptomic profiling revealed perturbations in gene sets associated with glutamatergic synaptic function. At the molecular level, we identified specific changes in the cAMP/PKA pathway pointing toward a hyperactive cAMP pathway in SETD1A+/- neurons. Finally, by pharmacologically targeting the cAMP pathway we were able to rescue the network deficits in SETD1A+/- cultures. Our results demonstrate a link between SETD1A and the cAMP-dependent pathway in human neurons.
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- 2021
21. The emerging role of chromatin remodelers in neurodevelopmental disorders: a developmental perspective
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Nael Nadif Kasri, Dirk Schubert, Britt Mossink, and Moritz Negwer
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Neurodevelopment ,Radial glia ,Review ,Biology ,Epigenesis, Genetic ,Histones ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Glutamatergic ,Transcriptional regulation ,0302 clinical medicine ,Intellectual disability ,medicine ,Animals ,Humans ,Epigenetics ,Molecular Biology ,030304 developmental biology ,Progenitor ,Neurons ,Pharmacology ,Chromatin accessibility ,0303 health sciences ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,DNA Helicases ,Neural progenitor ,Cell Biology ,Chromatin Assembly and Disassembly ,medicine.disease ,Chromatin ,Neurodevelopmental Disorders ,Molecular Medicine ,GABAergic ,Autism ,Protein Processing, Post-Translational ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Contains fulltext : 235071.pdf (Publisher’s version ) (Open Access) Neurodevelopmental disorders (NDDs), including intellectual disability (ID) and autism spectrum disorders (ASD), are a large group of disorders in which early insults during brain development result in a wide and heterogeneous spectrum of clinical diagnoses. Mutations in genes coding for chromatin remodelers are overrepresented in NDD cohorts, pointing towards epigenetics as a convergent pathogenic pathway between these disorders. In this review we detail the role of NDD-associated chromatin remodelers during the developmental continuum of progenitor expansion, differentiation, cell-type specification, migration and maturation. We discuss how defects in chromatin remodelling during these early developmental time points compound over time and result in impaired brain circuit establishment. In particular, we focus on their role in the three largest cell populations: glutamatergic neurons, GABAergic neurons, and glia cells. An in-depth understanding of the spatiotemporal role of chromatin remodelers during neurodevelopment can contribute to the identification of molecular targets for treatment strategies.
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- 2021
22. SETD1A Mediated H3K4 Methylation and Its Role in Neurodevelopmental and Neuropsychiatric Disorders
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Shan Wang, Anna Bleeck, Nael Nadif Kasri, Tjitske Kleefstra, Jon-Ruben van Rhijn, and Dirk Schubert
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Mini Review ,Neurosciences. Biological psychiatry. Neuropsychiatry ,neurodevelopmental disorders (NDD) ,Cellular and Molecular Neuroscience ,chromatin modification ,Intellectual disability ,Gene expression ,SETD1A ,medicine ,Enhancer ,Molecular Biology ,histone methlyation ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,biology ,Promoter ,medicine.disease ,Chromatin ,schizophrenia ,Histone ,psychiatric disorders ,Schizophrenia ,biology.protein ,Molecular Neuroscience ,Neuroscience ,Function (biology) ,RC321-571 - Abstract
Contains fulltext : 244082.pdf (Publisher’s version ) (Open Access) Posttranslational modification of histones and related gene regulation are shown to be affected in an increasing number of neurological disorders. SETD1A is a chromatin remodeler that influences gene expression through the modulation of mono- di- and trimethylation marks on Histone-H3-Lysine-4 (H3K4me1/2/3). H3K4 methylation is predominantly described to result in transcriptional activation, with its mono- di- and trimethylated forms differentially enriched at promoters or enhancers. Recently, dominant mostly de novo variants in SETD1A have clinically been linked to developmental delay, intellectual disability (DD/ID), and schizophrenia (SCZ). Affected individuals often display both developmental and neuropsychiatric abnormalities. The primary diagnoses are mainly dependent on the age at which the individual is assessed. Investigations in mouse models of SETD1A dysfunction have been able to recapitulate key behavioral features associated with ID and SCZ. Furthermore, functional investigations suggest disrupted synaptic and neuronal network function in these mouse models. In this review, we provide an overview of pre-clinical studies on the role of SETD1A in neuronal development. A better understanding of the pathobiology underlying these disorders may provide novel opportunities for therapeutic intervention. As such, we will discuss possible strategies to move forward in elucidating the genotype-phenotype correlation in SETD1A associated disorders.
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- 2021
23. KANSL1 Deficiency Causes Neuronal Dysfunction by Oxidative Stress-Induced Autophagy
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Lynn Devilee, Giuseppe Testa, Dirk Schubert, EIly I. Lewerissa, Nael Nadif Kasri, Monica Frega, Edda Ulferts, Michele Gabriele, Hans van Bokhoven, Katrin Linda, Chantal Schoenmaker, Teun M. Klein Gunnewiek, Anouk H.A. Verboven, Bert B.A. de Vries, David A. Koolen, and Astrid R. Oudakker
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Autophagosome ,chemistry.chemical_classification ,Reactive oxygen species ,biology ,Chemistry ,Autophagy ,medicine.disease_cause ,Cell biology ,Synapse ,Superoxide dismutase ,medicine.anatomical_structure ,Lysosome ,medicine ,biology.protein ,Oxidative stress ,PI3K/AKT/mTOR pathway - Abstract
Autophagy is a finely tuned process of programmed degradation and recycling of proteins and cellular components, which is crucial in neuronal function and synaptic integrity. Mounting evidence implicates chromatin remodelling in fine-tuning autophagy pathways. However, this epigenetic regulation is poorly understood in neurons. Here, we investigate the role in autophagy of KANSL1, a member of the nonspecific lethal complex, which acetylates histone H4 on lysine 16 (H4K16ac) to facilitate transcriptional activation. Loss-of-function of KANSL1 is strongly associated with the neurodevelopmental disorder Koolen-de Vries Syndrome (KdVS).Starting from KANSL1-deficient human induced-pluripotent stem cells, both from KdVS patients and genome-edited lines, we identified superoxide dismutase 1, an antioxidant enzyme, to be significantly decreased, leading to a subsequent increase in oxidative stress and autophagosome accumulation. In KANSL1-deficient neurons, autophagosome accumulation at excitatory synapses resulted in reduced synaptic density, reduced AMPA receptor-mediated transmission and impaired neuronal network activity. Furthermore, we found that increased oxidative stress-mediated autophagosome accumulation leads to increased mTOR activation and decreased lysosome function, further preventing the clearing of autophagosomes. Finally, by pharmacologically reducing oxidative stress, we could rescue the aberrant autophagosome formation as well as synaptic and neuronal network activity in KANSL1-deficient neurons. Our findings thus point towards an important relation between oxidative stress-induced autophagy and synapse function, and demonstrate the importance of H4K16ac-mediated changes in chromatin structure to balance reactive oxygen species- and mTOR-dependent autophagy.
- Published
- 2020
24. m.3243A > G-Induced Mitochondrial Dysfunction Impairs Human Neuronal Development and Reduces Neuronal Network Activity and Synchronicity
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Timothy J. Nelson, Noemi Vidal Folch, David Cassiman, Britt Mossink, Dirk Schubert, Monica Frega, Daan M. Panneman, Tamas Kozicz, Ester Perales-Clemente, Eva Morava, Eline J.H. van Hugte, Nael Nadif Kasri, Jason M. Keller, Katharina Foreman, Devin Oglesbee, Gemma Solé Guardia, Katrin Linda, Richard J. Rodenburg, T. M. Klein Gunnewiek, and Clinical Neurophysiology
- Subjects
0301 basic medicine ,Mitochondrial encephalomyopathy ,Alzheimer`s disease Donders Center for Medical Neuroscience [Radboudumc 1] ,induced pluripotent stem cells ,Mitochondrial disease ,Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13] ,Mitochondrion ,Biology ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Bursting ,All institutes and research themes of the Radboud University Medical Center ,0302 clinical medicine ,micro-electrode array ,medicine ,Biological neural network ,Animals ,Humans ,Rats, Wistar ,lcsh:QH301-705.5 ,Neurons ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,neurodevelopment ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,Cell Differentiation ,+G%22">m.3243A > G ,medicine.disease ,network activity ,Heteroplasmy ,neuron ,Rats ,mitochondria ,mitochondrial disease ,030104 developmental biology ,medicine.anatomical_structure ,lcsh:Biology (General) ,Lactic acidosis ,MELAS ,Neuron ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Summary: Epilepsy, intellectual and cortical sensory deficits, and psychiatric manifestations are the most frequent manifestations of mitochondrial diseases. How mitochondrial dysfunction affects neural structure and function remains elusive, mostly because of a lack of proper in vitro neuronal model systems with mitochondrial dysfunction. Leveraging induced pluripotent stem cell technology, we differentiated excitatory cortical neurons (iNeurons) with normal (low heteroplasmy) and impaired (high heteroplasmy) mitochondrial function on an isogenic nuclear DNA background from patients with the common pathogenic m.3243A > G variant of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). iNeurons with high heteroplasmy exhibited mitochondrial dysfunction, delayed neural maturation, reduced dendritic complexity, and fewer excitatory synapses. Micro-electrode array recordings of neuronal networks displayed reduced network activity and decreased synchronous network bursting. Impaired neuronal energy metabolism and compromised structural and functional integrity of neurons and neural networks could be the primary drivers of increased susceptibility to neuropsychiatric manifestations of mitochondrial disease. : Using human-inducible-pluripotent-stem-cell-derived neurons with high levels of m.3243A > G heteroplasmy, Klein Gunnewiek et al. show neuron-specific mitochondrial dysfunction as well as structural and functional impairments ranging from reduced dendritic complexity and fewer synapses and mitochondria to reduced neuronal activity and impaired network synchronicity. Keywords: MELAS, mitochondrial disease, mitochondria, neuron, induced pluripotent stem cells, network activity, neurodevelopment, micro-electrode array, m.3243A > G
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- 2020
25. p120-catenin-dependent collective brain infiltration by glioma cell networks
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Bart A. Westerman, Anna C. Navis, Jan Hendrik Venhuizen, Peter Friedl, Cindy E.J. Dieteren, Cornelia Veelken, Amparo Acker-Palmer, William P.J. Leenders, Dirk Schubert, Pavlo G. Gritsenko, Nader Atlasy, Pieter Wesseling, Hendrik G. Stunnenberg, Thomas Wurdinger, Neurosurgery, CCA - Cancer biology and immunology, CCA - Imaging and biomarkers, Pathology, and Academic Medical Center
- Subjects
Delta Catenin ,RHOA ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,Cell ,Down-Regulation ,Biology ,Article ,Adherens junction ,03 medical and health sciences ,Diffuse Glioma ,0302 clinical medicine ,Cell Line, Tumor ,Glioma ,Cell Adhesion ,medicine ,Animals ,Phosphorylation ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17] ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Cadherin ,Neurogenesis ,Brain ,Catenins ,Adherens Junctions ,Cell Biology ,Cell cycle ,Cadherins ,Phosphoproteins ,medicine.disease ,Cell biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,biology.protein ,Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] - Abstract
Contains fulltext : 220594.pdf (Publisher’s version ) (Closed access) Diffuse brain infiltration by glioma cells causes detrimental disease progression, but its multicellular coordination is poorly understood. We show here that glioma cells infiltrate the brain collectively as multicellular networks. Contacts between moving glioma cells are adaptive epithelial-like or filamentous junctions stabilized by N-cadherin, β-catenin and p120-catenin, which undergo kinetic turnover, transmit intercellular calcium transients and mediate directional persistence. Downregulation of p120-catenin compromises cell-cell interaction and communication, disrupts collective networks, and both the cadherin and RhoA binding domains of p120-catenin are required for network formation and migration. Deregulating p120-catenin further prevents diffuse glioma cell infiltration of the mouse brain with marginalized microlesions as the outcome. Transcriptomics analysis has identified p120-catenin as an upstream regulator of neurogenesis and cell cycle pathways and a predictor of poor clinical outcome in glioma patients. Collective glioma networks infiltrating the brain thus depend on adherens junctions dynamics, the targeting of which may offer an unanticipated strategy to halt glioma progression.
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- 2020
26. C.3 Gebaute Umwelt – Wohnen und Lebensstile Dirk Schubert
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Dirk Schubert
- Published
- 2020
27. Transformación de zonas portuarias y costeras en desuso: Experiencias, posibilidades y problemas
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Dirk Schubert and Joaquín Borschers
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Urban Studies ,Geography ,Local economy ,Geography, Planning and Development ,Conservation ,Humanities ,Cartography - Abstract
espanolEl concepto de revitalizacion urbana se aplica a procesos y planteamientos muy diferentes relacionados con la actuacion sobre areas costeras y portuarias obsoletas de todo el mundo. Se trata de actuaciones todas ellas con una gran trascendencia sobre la estructura general de las ciudades pero, a menudo, sus objetivos son muy distintos e incluso contradictorios. El articulo analiza algunos de los proyectos de revitalizacion portuaria mas conocidos y los clasifica en funcion de su meta caracteristica: fortalecimiento de la economia local (Londres, Melbourne), reordenacion del espacio urbano (Boston, Shanghai, Hong Kong), rehabitalizacion urbana (Vancouver), practica de nuevas culturas de planeamiento (Nueva York, Rotterdam), desarrollo de nuevos usos (Oslo, Genova, Amsterdam) o recuperacion del patrimonio (Copenhage, Chicago). EnglishThe concept of revitalization can be applied to many different processes and approaches connected to the actions on the obsolete coast and harbour areas. All these actions have a very high impact over the general structures of cities, although quite often, their goals are different or even contradictories. This article analyzes some of the very well known harbour revitalization projects all over the world and makes a clear classification depending on their targets: strengthening of the local economy (London and Melbourne), urban apace redistribution (Boston, Shanghai, Hong Kong) urban rehabilitation (Vancouver), put into practice cultures of new planning (New York, Rotterdam) development of new uses (Oslo, Genoa, Amsterdam) heritage recovery (Copenhagen, Chicago).
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- 2018
28. Mitochondrial dysfunction impairs human neuronal development and reduces neuronal network activity and synchronicity
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Nael Nadif Kasri, David Cassiman, Daan M. Panneman, T. M. Klein Gunnewiek, Gemma Solé Guardia, Katrin Linda, Eva Morava, Timothy J. Nelson, Jason M. Keller, Eline J.H. van Hugte, Dirk Schubert, Katharina Foreman, Tamas Kozicz, Britt Mossink, Monica Frega, Richard J. Rodenburg, and Ester Perales-Clemente
- Subjects
Mitochondrial encephalomyopathy ,Bursting ,medicine.anatomical_structure ,Lactic acidosis ,Mitochondrial disease ,medicine ,Biological neural network ,Neuron ,Mitochondrion ,Biology ,medicine.disease ,Neuroscience ,Heteroplasmy - Abstract
SummaryEpilepsy, intellectual and cortical sensory deficits and psychiatric manifestations are among the most frequent manifestations of mitochondrial diseases. Yet, how mitochondrial dysfunction affects neural structure and function remains largely elusive. This is mostly due to the lack of a properin vitrotranslational neuronal model system(s) with impaired energy metabolism. Leveraging the induced pluripotent stem cell technology, from a cohort of patients with the common pathogenic m.3243A>G variant of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), we differentiated excitatory cortical neurons (iNeurons) with normal (low heteroplasmy) and impaired (high heteroplasmy) mitochondrial function on an isogenic nuclear DNA background. iNeurons with high levels of heteroplasmy exhibited mitochondrial dysfunction, delayed neural maturation, reduced dendritic complexity and fewer functional excitatory synapses. Micro-electrode array recordings of neuronal networks with high heteroplasmy displayed reduced network activity and decreased synchronous network bursting. The impaired neural energy metabolism of iNeurons compromising the structural and functional integrity of neurons and neural networks, could be the primary driver of increased susceptibility to neuropsychiatric manifestations of mitochondrial disease.
- Published
- 2019
29. Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome
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Dirk Schubert, Pankaj B. Agrawal, Diante E Stremmelaar, Christian Gilissen, Koen L.I. van Gassen, Kirsty McWalter, Margot R.F. Reijnders, Rolph Pfundt, Alicia Casey, Jamie M Kramer, Tjitske Kleefstra, Olaf Bodamer, Eva Maria Christina Schwaibold, Annick Raas-Rothschild, Paulien A Terhal, Margje Sinnema, Nicholas Raun, Angela Bahr, Casie A. Genetti, Joost Kummeling, Trevor L Hoffman, James W. Wheless, Megan T. Cho, Martina Ruiterkamp-Versteeg, Velibor Tasic, Jasper J. van der Smagt, Katharina Steindl, Marleen Simon, Isabelle Thiffault, Pascal Joset, Elmar Keller, Marga Schepens, Marjolein H. Willemsen, Korbinian M. Riedhammer, David A. Koolen, Martin R. Higgs, Julia Hoefele, Nina Powell-Hamilton, Anita Rauch, Deniz Top, Dihong Zhou, Kendra Engleman, Calvin C O C O Man, MUMC+: DA KG Polikliniek (9), and RS: FHML non-thematic output
- Subjects
0301 basic medicine ,Microcephaly ,Methyltransferase ,HISTONE H3K4 METHYLASES ,PROTEIN ,Haploinsufficiency ,OF-FUNCTION VARIANTS ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Neurodevelopmental disorder ,Intellectual Disability ,SCHIZOPHRENIA ,medicine ,Animals ,Humans ,Global developmental delay ,Allele ,Child ,Molecular Biology ,030304 developmental biology ,Genetics ,0303 health sciences ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,biology ,COMPASS FAMILY ,GENETIC-VARIATION ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,Histone-Lysine N-Methyltransferase ,medicine.disease ,biology.organism_classification ,SELFISH SPERMATOGONIAL SELECTION ,Psychiatry and Mental health ,030104 developmental biology ,Drosophila melanogaster ,PATERNAL AGE ,DE-NOVO MUTATIONS ,Neurodevelopmental Disorders ,Histone methyltransferase ,Drosophila ,030217 neurology & neurosurgery - Abstract
Defects in histone methyltransferases (HMTs) are major contributing factors in neurodevelopmental disorders (NDDs). Heterozygous variants of SETD1A involved in histone H3 lysine 4 (H3K4) methylation were previously identified in individuals with schizophrenia. Here, we define the clinical features of the Mendelian syndrome associated with haploinsufficiency of SETD1A by investigating 15 predominantly pediatric individuals who all have de novo SETD1A variants. These individuals present with a core set of symptoms comprising global developmental delay and/or intellectual disability, subtle facial dysmorphisms, behavioral and psychiatric problems. We examined cellular phenotypes in three patient derived lymphoblastoid cell lines with three variants: p.Gly535Alafs*12, c.4582-2_4582delAG, and p.Tyr1499Asp. These patient cell lines displayed DNA damage repair defects that were comparable to previously observed RNAi-mediated depletion of SETD1A. This suggested that these variants, including the p.Tyr1499Asp in the catalytic SET domain, behave as Loss-of-Function (LoF) alleles. Previous studies demonstrated a role for SETD1A in cell cycle control and differentiation. However, individuals with SETD1A variants do not show major structural brain defects or severe microcephaly, suggesting that defective proliferation and differentiation of neural progenitors is unlikely the single underlying cause of the disorder. We show here that the Drosophila Melanogaster SETD1A orthologue is required in postmitotic neurons of the fly brain for normal memory, suggesting a role in post development neuronal function. Together, this study defines a neurodevelopmental disorder caused by dominant de novo LoF variants in SETD1A and further supports a role for H3K4 methyltransferases in the regulation of neuronal processes underlying normal cognitive functioning.
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- 2019
30. Neuronal network dysfunction in a human model for Kleefstra syndrome mediated by enhanced NMDAR signaling
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Monica Frega, Moritz Negwer, Teun M. Klein Gunnewiek, Güvem Gümüş-Akay, Astrid R. Oudakker, Katharina Foreman, Britt Mossink, Jason M. Keller, Nine Kompier, Nael Nadif Kasri, Willem M.R. van den Akker, Huiqing Zhou, Jon-Ruben van Rhijn, Tjitske Kleefstra, Dirk Schubert, Hans van Bokhoven, Chantal Schoenmaker, and Katrin Linda
- Subjects
GRIN1 ,Biology ,medicine.disease ,EHMT1 ,Neurodevelopmental disorder ,nervous system ,Histone methyltransferase ,Biological neural network ,medicine ,biology.protein ,Epigenetics ,Induced pluripotent stem cell ,Neuroscience ,Kleefstra Syndrome - Abstract
Epigenetic regulation of gene transcription plays a critical role in neural network development and in the etiology of Intellectual Disability (ID) and Autism Spectrum Disorder (ASD). However, little is known about the mechanisms by which epigenetic dysregulation leads to neural network defects. Kleefstra syndrome (KS), caused by mutation in the histone methyltransferase EHMT1, is a neurodevelopmental disorder with the clinical features of both ID and ASD. To study the impact of decreased EHMT1 function in human cells, we generated excitatory cortical neurons from induced pluripotent stem (iPS) cells derived from KS patients. In addition, we created an isogenic set by genetically editing healthy iPS cells. Characterization of the neurons at the single-cell and neuronal network level revealed consistent discriminative properties that distinguished EHMT1-mutant from wildtype neurons. Mutant neuronal networks exhibited network bursting with a reduced rate, longer duration, and increased temporal irregularity compared to control networks. We show that these changes were mediated by the upregulation of the NMDA receptor (NMDAR) subunit 1 and correlate with reduced deposition of the repressive H3K9me2 mark, the catalytic product of EHMT1, at the GRIN1 promoter. Furthermore, we show that EHMT1 deficiency in mice leads to similar neuronal network impairments and increased NMDAR function. Finally, we could rescue the KS patient-derived neuronal network phenotypes by pharmacological inhibition of NMDARs. Together, our results demonstrate a direct link between EHMT1 deficiency in human neurons and NMDAR hyperfunction, providing the basis for a more targeted therapeutic approach to treating KS.
- Published
- 2019
31. Neuronal network dysfunction in a model for Kleefstra syndrome mediated by enhanced NMDAR signaling
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Huiqing Zhou, Tjitske Kleefstra, Teun M. Klein Gunnewiek, Astrid R. Oudakker, Dirk Schubert, Moritz Negwer, Hans van Bokhoven, Ilse M. van der Werf, Katharina Foreman, Monica Frega, Jon-Ruben van Rhijn, Güvem Gümüş-Akay, Katrin Linda, Nael Nadif Kasri, Chantal Schoenmaker, Nine Kompier, Britt Mossink, Jason M. Keller, Willem M.R. van den Akker, and Clinical Neurophysiology
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0301 basic medicine ,Male ,General Physics and Astronomy ,Craniofacial Abnormalities ,Mice ,0302 clinical medicine ,Loss of Function Mutation ,Induced pluripotent stem cell ,lcsh:Science ,Kleefstra Syndrome ,Cerebral Cortex ,Neurons ,Multidisciplinary ,Developmental disorders ,Up-Regulation ,Reconstructive and regenerative medicine Radboud Institute for Molecular Life Sciences [Radboudumc 10] ,Histone methyltransferase ,NMDA receptor ,Female ,Molecular Developmental Biology ,Chromosome Deletion ,Chromosomes, Human, Pair 9 ,Heart Defects, Congenital ,Science ,Induced Pluripotent Stem Cells ,Primary Cell Culture ,Nerve Tissue Proteins ,Biology ,Molecular neuroscience ,Receptors, N-Methyl-D-Aspartate ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,EHMT1 ,All institutes and research themes of the Radboud University Medical Center ,Downregulation and upregulation ,Intellectual Disability ,Biological neural network ,Animals ,Humans ,Receptors, AMPA ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,GRIN1 ,General Chemistry ,Histone-Lysine N-Methyltransferase ,Cellular neuroscience ,Disease Models, Animal ,030104 developmental biology ,nervous system ,biology.protein ,lcsh:Q ,Dizocilpine Maleate ,Neuroscience ,Excitatory Amino Acid Antagonists ,030217 neurology & neurosurgery - Abstract
Kleefstra syndrome (KS) is a neurodevelopmental disorder caused by mutations in the histone methyltransferase EHMT1. To study the impact of decreased EHMT1 function in human cells, we generated excitatory cortical neurons from induced pluripotent stem (iPS) cells derived from KS patients. Neuronal networks of patient-derived cells exhibit network bursting with a reduced rate, longer duration, and increased temporal irregularity compared to control networks. We show that these changes are mediated by upregulation of NMDA receptor (NMDAR) subunit 1 correlating with reduced deposition of the repressive H3K9me2 mark, the catalytic product of EHMT1, at the GRIN1 promoter. In mice EHMT1 deficiency leads to similar neuronal network impairments with increased NMDAR function. Finally, we rescue the KS patient-derived neuronal network phenotypes by pharmacological inhibition of NMDARs. Summarized, we demonstrate a direct link between EHMT1 deficiency and NMDAR hyperfunction in human neurons, providing a potential basis for more targeted therapeutic approaches for KS., Kleefstra syndrome is a neurodevelopmental disorder associated with hapoinsufficiency of the histone methyltransferase EHMT1. Here the authors show using induced pluripotent cells-derived neurons from patients that network dysfunction occurs and is due to dysfunction of the NMDA receptor.
- Published
- 2019
32. Brain-on-a chip technologies for investigating neuronal diseases: Toward precision medicine applications
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Monica Frega, Dirk Schubert, Jason M. Keller, Katrin Linda, Nael Nadif Kasri, and B. Mossink
- Subjects
0301 basic medicine ,Biology ,medicine.disease ,Phenotype ,Hypotonia ,Synapse ,03 medical and health sciences ,030104 developmental biology ,Intellectual disability ,Biological neural network ,medicine ,medicine.symptom ,Stem cell ,Induced pluripotent stem cell ,Neuroscience ,Kleefstra Syndrome - Abstract
Neurodevelopmental disorders (NDDs) are a collection of heterogeneous syndromes involving disruption of early neurobiological development. While the identification of disease genes has great benefits for diagnostic and prognostic purposes, for the vast majority of these genes there is little knowledge about neurobiological mechanisms that they control at the cellular and network level. Recent studies demonstrate that NDDs are "diseases of the synapse". Synaptic malfunction can severely affect network connectivity and dynamic. Understanding the neural circuit basis of NDDs is therefore imperial for a better understanding of these disorders. Kleefstra syndrome (KS) is a NDD characterized by moderate to severe intellectual disability, childhood hypotonia, and facial dysmorphism associated with genes deficiency. Here, we studied how KS genes-deficiency affects neuronal network maturation using dissociated neuronal cultures (i.e. from rodent or KS patient induced pluripotent stem cells). Using micro-electrode arrays technology we characterized the electrophysiological activity of control and KS genes-deficient neuronal networks. We showed that KS genes-deficient neuronal networks exhibited different pattern of synchronous activity compared to control condition. In particular, KS genes-deficiency induced an inappropriate network organization and irregular pattern of activity, indicating that KS genes are required for proper network formation. The neuronal network phenotype found here, provides for relevant future directions in the elucidation of pathophysiology in KS.
- Published
- 2018
33. Holographic endoscope based on coherent fiber bundles and adaptive optics (Conference Presentation)
- Author
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Jürgen Czarske, Dirk Schubert, Robert Kuschmierz, and Nektarios Koukourakis
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Physics ,Spatial light modulator ,business.industry ,Holography ,Image plane ,law.invention ,Speckle pattern ,Optics ,Optical tweezers ,law ,Guide star ,Adaptive optics ,business ,Digital holography - Abstract
Coherent fiber bundles (CFB) are commonly used for endoscopic imaging, e.g. in biomedicine. Usually a CFB with several ten thousand cores is employed together with a lens system on its distal end. However, pixelation effects occur and the imaging plane can’t be scanned, limiting the field of application of CFBs. To circumvent these limitations, a spatial light modulator (SLM) is employed on the proximal side of a single-mode CFB. This enables creating arbitrary wave fronts at the distal fiber end, e.g. for instance for optical tweezers, endoscopes with tunable image plane or for exciting transgenetic nerve cells. However, of the shelf CFBs show phase distortions between individual cores (e.g. coupling between cores, speckle effect) which need to be calibrated and corrected at the proximal side. These distortions depend on the wavelength, temperature, polarization and most importantly on the bending of the CFB. Therefore an on-line calibration during bending variations is required. For this purpose a semitransparent mirror is employed at the distal fiber end, which allows to measure double the distortion at the proximal side by digital holography without the need for a guide star. For correcting the distortion the same SLM as above is employed. However, the distortion for a single transmission through the CFB commonly exceeds several 2 pi. Thus, an incremental phase measurement yields unambiguous results. To circumvent this problem, two approaches for on-line calibration are compared. 1st Multiple wavelength holography and 2nd initial calibration in transmission mode with subsequent tracking of distortion changes in reflecting mode.
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- 2018
34. Maternal depressive symptoms during pregnancy are associated with amygdala hyperresponsivity in children
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Tonya White, Floris Klumpers, Judith R. Homberg, Dirk Schubert, Hanan El Marroun, Noortje J. F. van der Knaap, Guillén Fernández, Vincent W. V. Jaddoe, Sabine E. Mous, Albert Hofman, and Henning Tiemeier
- Subjects
Male ,medicine.medical_specialty ,Offspring ,Population ,Emotions ,Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13] ,Mothers ,Neurophysiology ,Amygdala ,Experimental Psychopathology and Treatment ,03 medical and health sciences ,0302 clinical medicine ,All institutes and research themes of the Radboud University Medical Center ,Pregnancy ,Risk Factors ,130 000 Cognitive Neurology & Memory ,Developmental and Educational Psychology ,medicine ,Prenatal ,Humans ,Prospective Studies ,Risk factor ,Psychiatry ,education ,Child ,Depression (differential diagnoses) ,education.field_of_study ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Depression ,fMRI ,General Medicine ,Original Contribution ,medicine.disease ,Magnetic Resonance Imaging ,030227 psychiatry ,Psychiatry and Mental health ,medicine.anatomical_structure ,Pediatrics, Perinatology and Child Health ,Generation R ,Female ,Psychology ,030217 neurology & neurosurgery ,Psychopathology ,Clinical psychology - Abstract
Contains fulltext : 183010.pdf (Publisher’s version ) (Open Access) Depression during pregnancy is highly prevalent and has a multitude of potential risks of the offspring. Among confirmed consequences is a higher risk of psychopathology. However, it is unknown how maternal depression may impact the child's brain to mediate this vulnerability. Here we studied amygdala functioning, using task-based functional MRI, in children aged 6-9 years as a function of prenatal maternal depressive symptoms selected from a prospective population-based sample (The Generation R Study). We show that children exposed to clinically relevant maternal depressive symptoms during pregnancy (N = 19) have increased amygdala responses to negative emotional faces compared to control children (N = 20) [F(1,36) 7.02, p = 0.022]. Strikingly, postnatal maternal depressive symptoms, obtained at 3 years after birth, did not explain this relation. Our findings are in line with a model in which prenatal depressive symptoms of the mother are associated with amygdala hyperresponsivity in her offspring, which may represent a risk factor for later-life psychopathology. 8 p.
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- 2018
35. Neurons derived from induced pluripotent stem cells on microelectrode arrays: a human model for neurodevelopmental disorders
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Nael Nadif Kasri, Britt Mossink, Monica Frega, Dirk Schubert, Sebastian Van Gestel, Jason M. Keller, Katrin Linda, and Jon-Ruben van Rhijn
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Cellular and Molecular Neuroscience ,Microelectrode ,Chemistry ,Induced pluripotent stem cell ,Cell biology - Published
- 2018
36. Cell-type specific contribution to neuronal network (dys)function in neurodevelopmental disorders
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Sophie Janssen, Britt Mossink, Dirk Schubert, Nael Nadif Kasri, Katrin Linda, Chantal Schoenmaker, Jason M. Keller, Jon-Ruben van Rhijn, and Monica Frega
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Cellular and Molecular Neuroscience ,Cell type specific ,Biological neural network ,Biology ,Neuroscience ,Function (biology) - Published
- 2018
37. Human IPSC derived dopaminergic neurons show reduced activity following heterozygous FOXP2 knockout
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Nael Nadif Kasri, Dirk Schubert, Yan Shi, and Jon-Ruben van Rhijn
- Subjects
Cellular and Molecular Neuroscience ,Dopaminergic ,FOXP2 ,Biology ,Neuroscience - Published
- 2018
38. Ports and Urban Waterfronts
- Author
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Dirk Schubert
- Subjects
Geography - Published
- 2017
39. Opposition, Participation, and Community-Driven Planning Histories
- Author
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Dirk Schubert
- Subjects
Politics ,Urban planning ,media_common.quotation_subject ,Political science ,Opposition (politics) ,Legislature ,Public administration ,Modernization theory ,Democracy ,Built environment ,Social movement ,media_common - Abstract
This chapter focuses on developments in democratic and pluralistic societies. Participation and community-driven planning were topics of debate after World War II, in light of increasing problems with housing and other issues in cities all over the world. Democratic rule is based on political equality and participation rights—although these are not about participation at the housing and building level, but at district and city level, and about having a say in the planning and design of the built environment. In representative democracies with legislative, executive, and judicial authorities, governments formed at various levels by elected politicians are responsible for political decisions, which include planning, land, and building laws. The social movements are the product and producers of modernization, and urban planning history is a victorious history of "successful" modernization processes. For urban planning history, it is important to contextualize stakeholders, projects, and plans before a socio-political background, and to integrate transdisciplinary and comparative approaches.
- Published
- 2017
40. Path Dependencies Managing the River Elbe and the Requirements of Hamburg’s Open Tidal Seaport
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Dirk Schubert
- Published
- 2017
41. V1 connections reveal a series of elongated higher visual areas in the California ground squirrel, Otospermophilus beecheyi
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Dirk Schubert, David C. Lyon, Moritz Negwer, and Yong-Jun Liu
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Male ,0301 basic medicine ,Rodent ,genetic structures ,Neurophysiology ,Visual processing ,03 medical and health sciences ,Imaging, Three-Dimensional ,0302 clinical medicine ,biology.animal ,Cortex (anatomy) ,Image Processing, Computer-Assisted ,medicine ,Animals ,Visual Pathways ,Primate ,Visual Cortex ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,biology ,General Neuroscience ,Sciuridae ,biology.organism_classification ,Retrograde tracing ,eye diseases ,030104 developmental biology ,California ground squirrel ,Visual cortex ,medicine.anatomical_structure ,Female ,Otospermophilus beecheyi ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Item does not contain fulltext For studies of visual cortex organization, mouse is becoming an increasingly more often used model. In addition to its genetic tractability, the relatively small area of cortical surface devoted to visual processing simplifies efforts in relating the structure of visual cortex to visual function. However, the nature of this compact organization can make some comparisons to the much larger non-human primate visual cortex difficult. The squirrel, as a highly visual rodent offers a useful means for better understanding how mouse and monkey cortical organization compares. More in line with primates than their nocturnal rodent cousin, squirrels rely much more on sight and have evolved a larger expanse of cortex devoted to visual processing. To reveal the detailed organization of visual cortex in squirrels, we injected a highly sensitive monosynaptic retrograde tracer (glycoprotein deleted rabies virus) into several locations of primary visual cortex (V1) in California ground squirrels. The resulting pattern of connectivity revealed an organizational scheme in the squirrel that retains some of the basic features of the mouse visual cortex along the medial and posterior borders of V1, but unlike mouse has an elaborate and extensive pattern laterally that is more similar to the early visual cortex organization found in monkeys. In this way, we show that the squirrel can serve as a useful model for comparison to both mouse and primate visual systems, and may help facilitate comparisons between these two very different yet widely used animal models of visual processing. 13 p.
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- 2017
42. FOXP2 drives neuronal differentiation by interacting with retinoic acid signaling pathways
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Dirk Schubert and Moritz Negwer
- Subjects
0301 basic medicine ,neurite outgrowth ,forkhead transcription factors ,striatum ,Retinoic acid ,Striatum ,Biology ,Medium spiny neuron ,speech disorder ,SH-SY5Y cells ,motor circuits ,RARB ,03 medical and health sciences ,chemistry.chemical_compound ,globus pallidus ,Dopamine ,FoxP2 ,medicine ,retinoic acid ,Original Research Article ,neuron differentiation ,GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries) ,neuronal migration ,language ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,General Neuroscience ,FOXP2 ,030104 developmental biology ,Globus pallidus ,chemistry ,Frontiers Commentary ,Speech disorder ,Convergence (relationship) ,medicine.symptom ,dopamine ,Neuroscience ,medicine.drug - Abstract
FOXP2 was the first gene shown to cause a Mendelian form of speech and language disorder. Although developmentally expressed in many organs, loss of a single copy of FOXP2 leads to a phenotype that is largely restricted to orofacial impairment during articulation and linguistic processing deficits. Why perturbed FOXP2 function affects specific aspects of the developing brain remains elusive. We investigated the role of FOXP2 in neuronal differentiation and found that FOXP2 drives molecular changes consistent with neuronal differentiation in a human model system. We identified a network of FOXP2 regulated genes related to retinoic acid signaling and neuronal differentiation. FOXP2 also produced phenotypic changes associated with neuronal differentiation including increased neurite outgrowth and reduced migration. Crucially, cells expressing FOXP2 displayed increased sensitivity to retinoic acid exposure. This suggests a mechanism by which FOXP2 may be able to increase the cellular differentiation response to environmental retinoic acid cues for specific subsets of neurons in the brain. These data demonstrate that FOXP2 promotes neuronal differentiation by interacting with the retinoic acid signaling pathway and regulates key processes required for normal circuit formation such as neuronal migration and neurite outgrowth. In this way, FOXP2, which is found only in specific subpopulations of neurons in the brain, may drive precise neuronal differentiation patterns and/or control localization and connectivity of these FOXP2 positive cells.
- Published
- 2017
43. Impedance Spectrum in Cortical Tissue: Implications for Propagation of LFP Signals on the Microscopic Level
- Author
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Gaute T. Einevoll, Dirk Schubert, Stéphanie Miceli, and Torbjørn V. Ness
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Male ,Patch-Clamp Techniques ,multielectrode array ,Frequency band ,Models, Neurological ,Neurophysiology ,Neuronal Excitability ,Local field potential ,Biology ,Sodium Chloride ,Somatosensory system ,Signal ,Tissue Culture Techniques ,03 medical and health sciences ,0302 clinical medicine ,Electric Impedance ,Animals ,Rats, Wistar ,signal frequency ,GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries) ,030304 developmental biology ,0303 health sciences ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,local field potential ,General Neuroscience ,General Medicine ,Multielectrode array ,Somatosensory Cortex ,New Research ,neuronal tissue ,Electric Stimulation ,Cortex (botany) ,Electrophysiology ,Microelectrode ,cortex ,conductivity ,Extracellular Space ,Microelectrodes ,030217 neurology & neurosurgery ,Biomedical engineering - Abstract
Visual Abstract, Brain research investigating electrical activity within neural tissue is producing an increasing amount of physiological data including local field potentials (LFPs) obtained via extracellular in vivo and in vitro recordings. In order to correctly interpret such electrophysiological data, it is vital to adequately understand the electrical properties of neural tissue itself. An ongoing controversy in the field of neuroscience is whether such frequency-dependent effects bias LFP recordings and affect the proper interpretation of the signal. On macroscopic scales and with large injected currents, previous studies have found various grades of frequency dependence of cortical tissue, ranging from negligible to strong, within the frequency band typically considered relevant for neuroscience (less than a few thousand hertz). Here, we performed a detailed investigation of the frequency dependence of the conductivity within cortical tissue at microscopic distances using small current amplitudes within the typical (neuro)physiological micrometer and sub-nanoampere range. We investigated the propagation of LFPs, induced by extracellular electrical current injections via patch-pipettes, in acute rat brain slice preparations containing the somatosensory cortex in vitro using multielectrode arrays. Based on our data, we determined the cortical tissue conductivity over a 100-fold increase in signal frequency (5–500 Hz). Our results imply at most very weak frequency-dependent effects within the frequency range of physiological LFPs. Using biophysical modeling, we estimated the impact of different putative impedance spectra. Our results indicate that frequency dependencies of the order measured here and in most other studies have negligible impact on the typical analysis and modeling of LFP signals from extracellular brain recordings.
- Published
- 2017
- Full Text
- View/download PDF
44. 'Open City' – From 'Eyes on the Street' to 'Zero Tolerance'. Jane Jacobs’ Visionen einer sichereren Stadt
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Dirk Schubert
- Subjects
History ,Law ,Humanities - Abstract
Stadt und Sicherheit sind kein neues Thema. Uber viele Jahrhunderte hinweg bot die Stadt „innerhalb der Mauern“ relative „Sicherheit“ und Aufstiegs- und Wohlstandsperspektiven in okonomischer und sozialer Hinsicht. Im 19. Jahrhundert wurden im Kontext von Migration, Elendsvierteln und Wohnungsnot Themen von ethnischen Minderheiten, von abweichendem Verhalten und Kriminalitat in vielerlei Auspragungen Begleiterscheinungen des Urbanisierungsprozesses.
- Published
- 2016
45. F12AGGRESSION IN A DISH: A HUMAN MODEL FOR BRUNNER SYNDROME REVEALS INCREASED NEURONAL NETWORK ACTIVITY OF DOPAMINERGIC NEURONS
- Author
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Maren Bormann, Jon-Ruben van Rhijn, Jason M. Keller, Dirk Schubert, Monica Frega, Nael Nadif Kasri, Yan Shi, Han G. Brunner, Marina Hakobjan, Britt Mossink, Sarah Kittel-Schneider, and Barbara Franke
- Subjects
Pharmacology ,Psychiatry and Mental health ,Neurology ,Brunner syndrome ,Dopaminergic ,Biological neural network ,medicine ,Pharmacology (medical) ,Neurology (clinical) ,Biology ,medicine.disease ,Neuroscience ,Biological Psychiatry - Published
- 2019
46. IPHS Book Prize 2012: winners honoured in Sao Paulo
- Author
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Dirk Schubert
- Subjects
Political science ,Political economy ,Geography, Planning and Development ,Economic history - Published
- 2013
47. Aufwertung ohne Verdrängung
- Author
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Dirk Schubert
- Abstract
Vor dem Hintergrund wachsender sozialer Ungleichheit und sozialraumlicher Polarisierung in deutschen Grosstadten besteht an empirischen Studien zur Aufwertung, Gentrifizierung und sozialer Entmischung von Stadtquartieren kein Mangel und die Gefahren einer soziookonomischen Polarisierung der Stadte sind in Forschung und Politik hinreichend bekannt (vgl. BMVBS, 2009). Die Untersuchungen eint, dass aktuelle Veranderungsprozesse der Wohnbedingungen und des Einzelhandels detailliert beschrieben – praziser beklagt – werden, aber keine Studien bestehen, welche die Ausgangssituation eines (noch) nicht aufgewertet Viertels analysieren und mittels einer Langsschnittstudie mit gleichen Daten eine fundierte Ex-post-Analyse ermoglichen wurden. Sicher wurde die Immobilienwirtschaft derartige Identifizierungen von „Truffelschweinen der Stadtentwicklung“ fur „Gentrifizierungsgebiete im Wartezustand“ zu gerne aufgreifen, waren doch damit erhebliche Gewinnspannen zu erzielen.
- Published
- 2016
48. Contemporary Perspectives on Jane Jacobs
- Author
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Dirk Schubert
- Published
- 2016
49. The safety of medical devices containing DEHP plasticized PVC or other plasticizers on neonates and other groups possibly at risk (2015 update)
- Author
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Emanuela Testai, Philippe Hartemann, Suresh Chandra Rastogi, Ulrike Bernauer, Aldert Piersma, Wim De Jong, Hans Gulliksson, Richard Sharpe, Dirk Schubert, Eduardo Rodríguez-Farre, Michelle Epstein, Igor Emri, Peter Hoet, Norbert Leitgeb, Luis Martínez Martinez, Ana Proykova, Luigi Rizzo, Eduardo Rodriguez-Farré, Lesley Rushton, Konrad Rydzynski, Theodoros Samaras, and Theodorus Vermeire
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medicine.medical_specialty ,MEDLINE ,030204 cardiovascular system & hematology ,010501 environmental sciences ,Toxicology ,01 natural sciences ,Risk Assessment ,03 medical and health sciences ,Patient safety ,0302 clinical medicine ,Plasticizers ,Risk Factors ,Diethylhexyl Phthalate ,Toxicity Tests ,Medicine ,Animals ,Humans ,Polyvinyl Chloride ,0105 earth and related environmental sciences ,Equipment Safety ,business.industry ,Plasticizer ,Age Factors ,Infant, Newborn ,General Medicine ,Equipment Design ,Equipment and Supplies ,Emergency medicine ,Patient Safety ,business ,Risk assessment - Published
- 2016
50. Morphological Characteristics of Electrophysiologically Characterized Layer Vb Pyramidal Cells in Rat Barrel Cortex
- Author
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Jochen F. Staiger, Dirk Schubert, Martin Möck, and Alexandre J.C. Loucif
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Male ,0301 basic medicine ,Physiology ,Quantitative morphology ,Action Potentials ,lcsh:Medicine ,Signal ,Electrophysiological Properties ,Nerve Fibers ,0302 clinical medicine ,Animal Cells ,Medicine and Health Sciences ,lcsh:Science ,Neuronal dendrites ,Pyramidal cells ,Action potentials ,Neurons ,Axons ,Membrane potential ,Color codes ,Electrophysiological properties ,Multidisciplinary ,Neocortex ,Pyramidal Cells ,Anatomy ,Electrophysiology ,medicine.anatomical_structure ,Cellular Types ,Research Article ,Computer and Information Sciences ,Ganglion Cells ,Neurophysiology ,Biology ,Membrane Potential ,03 medical and health sciences ,medicine ,Animals ,Layer (object-oriented design) ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Data Visualization ,lcsh:R ,Biology and Life Sciences ,Dendrites ,Cell Biology ,Neuronal Dendrites ,Barrel cortex ,Electrophysiological Phenomena ,Rats ,Color Codes ,030104 developmental biology ,Cellular Neuroscience ,Action potential firing ,lcsh:Q ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Contains fulltext : 167954.PDF (Publisher’s version ) (Open Access) Layer Vb pyramidal cells are the major output neurons of the neocortex and transmit the outcome of cortical columnar signal processing to distant target areas. At the same time they contribute to local tactile information processing by emitting recurrent axonal collaterals into the columnar microcircuitry. It is, however, not known how exactly the two types of pyramidal cells, called slender-tufted and thick-tufted, contribute to the local circuitry. Here, we investigated in the rat barrel cortex the detailed quantitative morphology of biocytin-filled layer Vb pyramidal cells in vitro, which were characterized for their intrinsic electrophysiology with special emphasis on their action potential firing pattern. Since we stained the same slices for cytochrome oxidase, we could also perform layer- and column-related analyses. Our results suggest that in layer Vb the unambiguous action potential firing patterns "regular spiking (RS)" and "repetitive burst spiking (RB)" (previously called intrinsically burst spiking) correlate well with a distinct morphology. RS pyramidal cells are somatodendritically of the slender-tufted type and possess numerous local intralaminar and intracolumnar axonal collaterals, mostly reaching layer I. By contrast, their transcolumnar projections are less well developed. The RB pyramidal cells are somatodendritically of the thick-tufted type and show only relatively sparse local axonal collaterals, which are preferentially emitted as long horizontal or oblique infragranular collaterals. However, contrary to many previous slice studies, a substantial number of these neurons also showed axonal collaterals reaching layer I. Thus, electrophysiologically defined pyramidal cells of layer Vb show an input and output pattern which suggests RS cells to be more "locally segregating" signal processors whereas RB cells seem to act more on a "global integrative" scale.
- Published
- 2016
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