154 results on '"Dirk Schubert"'
Search Results
2. Loss-of-function variants in the schizophrenia risk gene SETD1A alter neuronal network activity in human neurons through the 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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CP: Neuroscience ,Biology (General) ,QH301-705.5 - Abstract
Summary: Heterozygous loss-of-function (LoF) mutations in SETD1A, which encodes a subunit of histone H3 lysine 4 methyltransferase, cause a neurodevelopmental syndrome and increase the risk for schizophrenia. Using CRISPR-Cas9, we generate excitatory/inhibitory neuronal networks from human induced pluripotent stem cells with a SETD1A heterozygous LoF mutation (SETD1A+/−). Our data show that SETD1A haploinsufficiency results in morphologically increased dendritic complexity and functionally increased bursting activity. This network phenotype is primarily driven by SETD1A haploinsufficiency in glutamatergic neurons. In accordance with the functional changes, transcriptomic profiling reveals perturbations in gene sets associated with glutamatergic synaptic function. At the molecular level, we identify specific changes in the cyclic AMP (cAMP)/Protein Kinase A pathway pointing toward a hyperactive cAMP pathway in SETD1A+/− neurons. Finally, by pharmacologically targeting the cAMP pathway, we are 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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- 2022
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3. Perinatal SSRI exposure affects brain functional activity associated with whisker stimulation in adolescent and adult rats
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Noortje Van der Knaap, Dirk Wiedermann, Dirk Schubert, Mathias Hoehn, and Judith R. Homberg
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Medicine ,Science - Abstract
Abstract Selective serotonin reuptake inhibitors (SSRI), such as fluoxetine, are used as first-line antidepressant medication during pregnancy. Since SSRIs cross the placenta the unborn child is exposed to the maternal SSRI medication, resulting in, amongst others, increased risk for autism in offspring. This likely results from developmental changes in brain function. Studies employing rats lacking the serotonin transporter have shown that elevations in serotonin levels particularly affect the development of the whisker related part of the primary somatosensory (barrel) cortex. Therefore, we hypothesized that serotonin level disturbances during development alter brain activity related to whisker stimulation. We treated female dams with fluoxetine or vehicle from gestational day 11 onwards for 21 days. We investigated offspring’s brain activity during whisker stimulation using functional magnetic resonance imaging (fMRI) at adolescence and adulthood. Our results indicate that adolescent offspring displayed increased activity in hippocampal subareas and the mammillary body in the thalamus. Adult offspring exhibited increased functional activation of areas associated with (higher) sensory processing and memory such as the hippocampus, perirhinal and entorhinal cortex, retrospinal granular cortex, piriform cortex and secondary visual cortex. Our data imply that perinatal SSRI exposure leads to complex alterations in brain networks involved in sensory perception and processing.
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- 2021
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4. Brunner syndrome associated MAOA mutations result in NMDAR hyperfunction and increased network activity in human dopaminergic neurons
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Jon-Ruben van Rhijn, Yan Shi, Maren Bormann, Britt Mossink, Monica Frega, Hatice Recaioglu, Marina Hakobjan, Teun Klein Gunnewiek, Chantal Schoenmaker, Elizabeth Palmer, Laurence Faivre, Sarah Kittel-Schneider, Dirk Schubert, Han Brunner, Barbara Franke, and Nael Nadif Kasri
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Brunner syndrome ,MAOA ,Human iPSC ,Dopaminergic neuron ,NMDA receptor ,Microelectrode array ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Monoamine neurotransmitter abundance affects motor control, emotion, and cognitive function and is regulated by monoamine oxidases. Among these, Monoamine oxidase A (MAOA) catalyzes the degradation of dopamine, norepinephrine, and serotonin into their inactive metabolites. Loss-of-function mutations in the X-linked MAOA gene have been associated with Brunner syndrome, which is characterized by various forms of impulsivity, maladaptive externalizing behavior, and mild intellectual disability. Impaired MAOA activity in individuals with Brunner syndrome results in bioamine aberration, but it is currently unknown how this affects neuronal function, specifically in dopaminergic (DA) neurons. Here we generated human induced pluripotent stem cell (hiPSC)-derived DA neurons from three individuals with Brunner syndrome carrying different mutations and characterized neuronal properties at the single cell and neuronal network level in vitro. DA neurons of Brunner syndrome patients showed reduced synaptic density but exhibited hyperactive network activity. Intrinsic functional properties and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated synaptic transmission were not affected in DA neurons of individuals with Brunner syndrome. Instead, we show that the neuronal network hyperactivity is mediated by upregulation of the GRIN2A and GRIN2B subunits of the N-methyl-d-aspartate receptor (NMDAR), resulting in increased NMDAR-mediated currents. By correcting a MAOA missense mutation with CRISPR/Cas9 genome editing we normalized GRIN2A and GRIN2B expression, NMDAR function and neuronal population activity to control levels. Our data suggest that MAOA mutations in Brunner syndrome increase the activity of dopaminergic neurons through upregulation of NMDAR function, which may contribute to the etiology of Brunner syndrome associated phenotypes.
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- 2022
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5. 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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SETD1A ,neurodevelopmental disorders (NDD) ,psychiatric disorders ,chromatin modification ,histone methlyation ,schizophrenia ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
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
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6. Neuronal network dysfunction in a model for Kleefstra syndrome mediated by enhanced NMDAR signaling
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Monica Frega, Katrin Linda, Jason M. Keller, Güvem Gümüş-Akay, Britt Mossink, Jon-Ruben van Rhijn, Moritz Negwer, Teun Klein Gunnewiek, Katharina Foreman, Nine Kompier, Chantal Schoenmaker, Willem van den Akker, Ilse van der Werf, Astrid Oudakker, Huiqing Zhou, Tjitske Kleefstra, Dirk Schubert, Hans van Bokhoven, and Nael Nadif Kasri
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Science - Abstract
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.
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- 2019
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7. m.3243A > G-Induced Mitochondrial Dysfunction Impairs Human Neuronal Development and Reduces Neuronal Network Activity and Synchronicity
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Teun M. Klein Gunnewiek, Eline J.H. Van Hugte, Monica Frega, Gemma Solé Guardia, Katharina Foreman, Daan Panneman, Britt Mossink, Katrin Linda, Jason M. Keller, Dirk Schubert, David Cassiman, Richard Rodenburg, Noemi Vidal Folch, Devin Oglesbee, Ester Perales-Clemente, Timothy J. Nelson, Eva Morava, Nael Nadif Kasri, and Tamas Kozicz
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Biology (General) ,QH301-705.5 - 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
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8. Distinct Pathogenic Genes Causing Intellectual Disability and Autism Exhibit a Common Neuronal Network Hyperactivity Phenotype
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Monica Frega, Martijn Selten, Britt Mossink, Jason M. Keller, Katrin Linda, Rebecca Moerschen, Jieqiong Qu, Pierre Koerner, Sophie Jansen, Astrid Oudakker, Tjitske Kleefstra, Hans van Bokhoven, Huiqing Zhou, Dirk Schubert, and Nael Nadif Kasri
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Biology (General) ,QH301-705.5 - Abstract
Summary: Pathogenic mutations in either one of the epigenetic modifiers EHMT1, MBD5, MLL3, or SMARCB1 have been identified to be causative for Kleefstra syndrome spectrum (KSS), a neurodevelopmental disorder with clinical features of both intellectual disability (ID) and autism spectrum disorder (ASD). To understand how these variants lead to the phenotypic convergence in KSS, we employ a loss-of-function approach to assess neuronal network development at the molecular, single-cell, and network activity level. KSS-gene-deficient neuronal networks all develop into hyperactive networks with altered network organization and excitatory-inhibitory balance. Interestingly, even though transcriptional data reveal distinct regulatory mechanisms, KSS target genes share similar functions in regulating neuronal excitability and synaptic function, several of which are associated with ID and ASD. Our results show that KSS genes mainly converge at the level of neuronal network communication, providing insights into the pathophysiology of KSS and phenotypically congruent disorders. : Frega et al. show that mutations in functionally distinct genes leading to Kleefstra syndrome converge at the molecular, cellular, and neuronal network levels. KSS gene deficiency leads to hyperactive neuronal network communication and altered excitatory-inhibitory balance. Common biological pathways related to ion-channel expression and synaptic communication underlie this functional convergence. Keywords: Kleefstra syndrome spectrum, autism, intellectual disability, EHMT1, neurodevelopmental disorder, neuronal networks, micro-electrode arrays
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- 2020
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9. Biophysical Psychiatry—How Computational Neuroscience Can Help to Understand the Complex Mechanisms of Mental Disorders
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Tuomo Mäki-Marttunen, Tobias Kaufmann, Torbjørn Elvsåshagen, Anna Devor, Srdjan Djurovic, Lars T. Westlye, Marja-Leena Linne, Marcella Rietschel, Dirk Schubert, Stefan Borgwardt, Magdalena Efrim-Budisteanu, Francesco Bettella, Geir Halnes, Espen Hagen, Solveig Næss, Torbjørn V. Ness, Torgeir Moberget, Christoph Metzner, Andrew G. Edwards, Marianne Fyhn, Anders M. Dale, Gaute T. Einevoll, and Ole A. Andreassen
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genome-wide association study ,computational modelling ,ion channels ,schizophrenia ,psychotic disorders ,Psychiatry ,RC435-571 - Abstract
The brain is the most complex of human organs, and the pathophysiology underlying abnormal brain function in psychiatric disorders is largely unknown. Despite the rapid development of diagnostic tools and treatments in most areas of medicine, our understanding of mental disorders and their treatment has made limited progress during the last decades. While recent advances in genetics and neuroscience have a large potential, the complexity and multidimensionality of the brain processes hinder the discovery of disease mechanisms that would link genetic findings to clinical symptoms and behavior. This applies also to schizophrenia, for which genome-wide association studies have identified a large number of genetic risk loci, spanning hundreds of genes with diverse functionalities. Importantly, the multitude of the associated variants and their prevalence in the healthy population limit the potential of a reductionist functional genetics approach as a stand-alone solution to discover the disease pathology. In this review, we outline the key concepts of a “biophysical psychiatry,” an approach that employs large-scale mechanistic, biophysics-founded computational modelling to increase transdisciplinary understanding of the pathophysiology and strive toward robust predictions. We discuss recent scientific advances that allow a synthesis of previously disparate fields of psychiatry, neurophysiology, functional genomics, and computational modelling to tackle open questions regarding the pathophysiology of heritable mental disorders. We argue that the complexity of the increasing amount of genetic data exceeds the capabilities of classical experimental assays and requires computational approaches. Biophysical psychiatry, based on modelling diseased brain networks using existing and future knowledge of basic genetic, biochemical, and functional properties on a single neuron to a microcircuit level, may allow a leap forward in deriving interpretable biomarkers and move the field toward novel treatment options.
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- 2019
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10. Morphological Characteristics of Electrophysiologically Characterized Layer Vb Pyramidal Cells in Rat Barrel Cortex.
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Jochen F Staiger, Alexandre J C Loucif, Dirk Schubert, and Martin Möck
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Medicine ,Science - Abstract
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.
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- 2016
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11. Transformación de zonas portuarias y costeras en desuso: experiencias, posibilidades y problemas
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Dirk Schubert
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Disuse Harbour areas ,Urban revitalization ,Urban restructuring ,Industrial maritime heritage ,Cities. Urban geography ,GF125 - Abstract
The 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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- 2004
12. „Changing fast' — Transformationsprozesse in den Docklands in Dublin
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Dirk Schubert
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Cities. Urban geography ,GF125 ,Urbanization. City and country ,HT361-384 - Abstract
Policy and pracice perspective
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- 2006
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13. Revitalisierung von brachgefallenen Hafen- und Uferzonen
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Dirk Schubert
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Article ,Cities. Urban geography ,GF125 ,Urbanization. City and country ,HT361-384 - Abstract
In many ports, dockland areas close to the city centre have become available for urban redevelopment. This article discusses the transformation processes taking place in dockland and riverside zones within the context of the current discourse on urban-development policy; it also describes the renaissance and the transformation in the image of such zones. The author outlines the experience of the changes of use which these areas have undergone, the reasons that led to such sites becoming derelict, and the regeneration process; he also summarises the current state of academic analysis of the subject. Proceeding from a broad-based explanatory approach, the article sets out five phases of the transformation process affecting the relations between city and dockland, concluding with a brief restatement of the importance, the opportunities, problems and risks posed by the redevelopment of dockland and riverside areas.
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- 2002
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14. Brain-on-a chip technologies for investigating neuronal diseases: Toward precision medicine applications.
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M. Frega, B. Mossink, K. Linda, J. Keller, Dirk Schubert, and N. Nadif Kasri
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- 2018
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15. E/I balance in epilepsies and neurodevelopmental disorders: depolarizing <scp>GABA</scp> as a common mechanism
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Eline J. H. van Hugte, Dirk Schubert, and Nael Nadif Kasri
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Neurology ,Neurology (clinical) - Published
- 2023
16. 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
17. 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
18. 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
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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
19. 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.
- Published
- 2022
20. 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.
- Published
- 2021
21. Urban Hygiene and Slum Clearance as Catalysts
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Dirk Schubert
- Published
- 2022
22. Perinatal SSRI exposure affects brain functional activity associated with whisker stimulation in adolescent and adult rats
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Mathias Hoehn, Noortje J. F. van der Knaap, Dirk Wiedermann, Judith R. Homberg, and Dirk Schubert
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0301 basic medicine ,Male ,Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13] ,Hippocampus ,Stimulation ,Rats, Sprague-Dawley ,0302 clinical medicine ,Pregnancy ,Piriform cortex ,Cortex (anatomy) ,130 000 Cognitive Neurology & Memory ,Serotonin transporter ,Multidisciplinary ,biology ,Brain ,Magnetic Resonance Imaging ,Antidepressive Agents ,medicine.anatomical_structure ,Prenatal Exposure Delayed Effects ,Somatosensory system ,Medicine ,Female ,Selective Serotonin Reuptake Inhibitors ,medicine.medical_specialty ,Serotonin ,Offspring ,Science ,Thalamus ,Article ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,Internal medicine ,Fluoxetine ,medicine ,Animals ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,business.industry ,Development of the nervous system ,Entorhinal cortex ,Rats ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Vibrissae ,biology.protein ,business ,030217 neurology & neurosurgery - Abstract
Selective serotonin reuptake inhibitors (SSRI), such as fluoxetine, are used as first-line antidepressant medication during pregnancy. Since SSRIs cross the placenta the unborn child is exposed to the maternal SSRI medication, resulting in, amongst others, increased risk for autism in offspring. This likely results from developmental changes in brain function. Studies employing rats lacking the serotonin transporter have shown that elevations in serotonin levels particularly affect the development of the whisker related part of the primary somatosensory (barrel) cortex. Therefore, we hypothesized that serotonin level disturbances during development alter brain activity related to whisker stimulation. We treated female dams with fluoxetine or vehicle from gestational day 11 onwards for 21 days. We investigated offspring’s brain activity during whisker stimulation using functional magnetic resonance imaging (fMRI) at adolescence and adulthood. Our results indicate that adolescent offspring displayed increased activity in hippocampal subareas and the mammillary body in the thalamus. Adult offspring exhibited increased functional activation of areas associated with (higher) sensory processing and memory such as the hippocampus, perirhinal and entorhinal cortex, retrospinal granular cortex, piriform cortex and secondary visual cortex. Our data imply that perinatal SSRI exposure leads to complex alterations in brain networks involved in sensory perception and processing.
- Published
- 2021
23. Matching Spatial with Ontological Brain Regions using Java Tools for Visualization, Database Access, and Integrated Data Analysis.
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Gleb Bezgin, Andrew T. Reid, Dirk Schubert, and Rolf Kötter
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- 2009
- Full Text
- View/download PDF
24. Classification of cortical microcircuits based on micro-electrode-array data from slices of rat barrel cortex.
- Author
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Rembrandt Bakker, Dirk Schubert, Koen Levels, Gleb Bezgin, Ingo Bojak, and Rolf Kötter
- Published
- 2009
- Full Text
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25. 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.
- Published
- 2020
26. 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...
- Published
- 2020
27. Paths to the Green City: On the Work of Fritz Schumacher
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Dirk Schubert
- Published
- 2022
28. 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
29. 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
- Subjects
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
30. Separating burst from Background Spikes in multichannel neuronal recordings using Return Map Analysis.
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Marijn B. Martens, Michela Chiappalone, Dirk Schubert, and Paul H. E. Tiesinga
- Published
- 2014
- Full Text
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31. Städtebau unter Salazar. Diktatorische Modernisierung des portugiesischen Imperiums 1926–1960
- Author
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Dirk Schubert
- Subjects
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...
- Published
- 2020
32. Manuale zum Städtebau. Die Systematisierung des Wissens von der Stadt 1870–1950
- Author
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Dirk Schubert
- Subjects
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...
- Published
- 2020
33. International comparison of thermal noise-temperature measurements at 2, 4, and 12 GHz.
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James P. Randa, Joseph Achkar, Friedrich-Immanuel Buchholz, Thierry Colard, John Rice, Dirk Schubert, M. Sinclair, and Gareth L. Williams
- Published
- 1999
- Full Text
- View/download PDF
34. Jane Jacobs, cities, urban planning, ethics and value systems
- Author
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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.
- Published
- 2019
35. Entangled Urbanisms
- Author
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Dirk Schubert
- Subjects
Urban Studies ,History ,Sociology and Political Science - Published
- 2019
36. Glucocorticoid enhancement of recognition memory via basolateral amygdala-driven facilitation of prelimbic cortex interactions
- Author
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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
- Subjects
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.
- Published
- 2019
37. Cities and plans – the past defines the future
- Author
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Dirk Schubert
- Subjects
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
38. 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
- Subjects
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.
- Published
- 2021
39. 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.
- Published
- 2021
40. 'The Hoist of the Yellow Flag'
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Carola Hein, Cor Wagenaar, and Dirk Schubert
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medicine.medical_specialty ,Public health ,Geography, Planning and Development ,public health ,Public administration ,port cities ,Port (computer networking) ,Hamburg ,Rotterdam ,London ,medicine ,Key (cryptography) ,Hoist (device) ,Business ,Flag (geometry) - Abstract
Port cities have long played a key role in the development, discovery, and fight against diseases. They have been laboratories for policies to address public health issues. Diseases reached port cities through maritime exchanges, and the bubonic plague is a key example. Port city residents’ close contact with water further increased the chance for diseases such as cholera. Analyzing three European port cities, this article first explores the relevance of water quality for public health through the lens of the Dutch city of Rotterdam. It then examines plans and projects for London that were shaped by social Darwinism and stressed the moral failings of slum dwellers as a major cause for their misery. It finally explores the case of Hamburg as the perfect example of a city that cultivated ideals of purity and cleanliness by addressing all issues at stake in public health. This article on urban hygiene in three port cities shows how remarkably rich this field of study is; it also demonstrates that the multifaceted aspects of public health in port cities require further attention.
- Published
- 2021
41. Brunner syndrome associated MAOA dysfunction in human dopaminergic neurons results in NMDAR hyperfunction and increased network activity
- Author
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Britt Mossink, Elizabeth E. Palmer, Marina Hakobjan, Barbara Franke, Maren Bormann, Jon-Ruben van Rhijn, Yan Shi, Monica Frega, Chantal Schoenmaker, Nael Nadif Kasri, Han G. Brunner, Sarah Kittel-Schneider, Dirk Schubert, Teun M. Klein Gunnewiek, Hatice Recaioglu, and Laurence Faivre
- Subjects
Brunner syndrome ,Dopaminergic ,Biology ,medicine.disease ,Norepinephrine ,Monoamine neurotransmitter ,Dopamine ,biology.protein ,medicine ,GRIN2B ,Serotonin ,Monoamine oxidase A ,Neuroscience ,medicine.drug - Abstract
BackgroundMonoamine neurotransmitter abundance affects motor control, emotion, and cognitive function and is regulated by monoamine oxidases. Amongst these, monoamine oxidase A (MAOA) catalyzes the degradation of dopamine, norepinephrine, and serotonin into their inactive metabolites. Loss-of-function mutations in the X-linked MAOA gene cause Brunner syndrome, which is characterized by various forms of impulsivity, maladaptive externalizing behavior, and mild intellectual disability. Impaired MAOA activity in individuals with Brunner syndrome results in bioamine aberration, but it is currently unknown how this affects neuronal function.MethodsWe generated human induced pluripotent stem cell (hiPSC)-derived dopaminergic (DA) neurons from three individuals with Brunner syndrome carrying different mutations, and used CRISPR/Cas9 mediated homologous recombination to rescue MAOA function. We used these lines to characterize morphological and functional properties of DA neuronal cultures at the single cell and neuronal network level in vitro.ResultsBrunner syndrome DA neurons showed reduced synaptic density but hyperactive network activity. Intrinsic functional properties and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated synaptic transmission were not affected by MAOA dysfunction. Instead, we show that the neuronal network hyperactivity is mediated by upregulation of the GRIN2A and GRIN2B subunits of the N-methyl-D-aspartate receptor (NMDAR), and rescue of MAOA results in normalization of NMDAR function as well as restoration of network activity.ConclusionsOur data suggest that MAOA dysfunction in Brunner syndrome increases activity of dopaminergic neurons through upregulation of NMDAR function, which may contribute to Brunner syndrome associated phenotypes.
- Published
- 2020
42. KANSL1 Deficiency Causes Neuronal Dysfunction by Oxidative Stress-Induced Autophagy
- Author
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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
- Subjects
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
43. Cadherin-13 is a critical regulator of GABAergic modulation in human stem cell derived neuronal networks
- Author
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Alessia Anania, Sophie Jansen, Jon-Ruben van Rhijn, Hans van Bokhoven, Nael Nadif Kasri, Katrin Linda, Britt Mossink, Anouk H.A. Verboven, Jitske Bak, Dirk Schubert, Teun M. Klein Gunnewiek, Shan Wang, Eline J.H. van Hugte, Jason M. Keller, Monica Frega, Astrid R. Oudakker, Martijn Selten, and Chantal Schoenmaker
- Subjects
education.field_of_study ,Glutamatergic ,biology ,Cadherin ,Population ,biology.protein ,Regulator ,GABAergic ,Stem cell ,Inhibitory postsynaptic potential ,education ,Neuroscience ,Parvalbumin - Abstract
SummaryActivity in the healthy brain relies on 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 human patient, has typically been hampered by methodological limitations.Cadherin-13(CDH13) has strongly been associated to attention-deficit/hyperactivity disorder and comorbid disorders such as autism and schizophrenia. CDH13 localises 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 PV 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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- 2020
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44. m.3243A > G-Induced Mitochondrial Dysfunction Impairs Human Neuronal Development and Reduces Neuronal Network Activity and Synchronicity
- Author
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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
45. p120-catenin-dependent collective brain infiltration by glioma cell networks
- Author
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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
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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
46. Resilience, Disaster, and Rebuilding in Modern Port Cities
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Carola Hein and Dirk Schubert
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Value (ethics) ,History ,Sociology and Political Science ,vulnerability ,Vulnerability ,Face (sociological concept) ,Historiography ,port cities ,sustainability ,Port (computer networking) ,Urban Studies ,Economy ,Section (archaeology) ,Political science ,disaster ,Sustainability ,rebuilding ,Resilience (network) ,resilience - Abstract
Resilience has become a buzzword used to describe the capacity of cities to bounce back after disasters. It carries the hope of a robust and more sustainable future. Disasters can strike any region, but port cities face complex and particular risks due to their location at the intersection of sea and land, and their role in an international maritime system. This introduction to the special section on resilience, disaster and rebuilding in modern port cities first examines resilience as a concept and course of action in a heterogenous theory landscape. It then explores different dimensions of resilience—environmental, economic, institutional, social and spatial—and their importance in port city historiography. The articles collected in this special section explore case studies from three continents. Together, they demonstrate that there is no such thing as the resilient (port) city. But, they also show that the combination of maritime and urban interests can lead to creative planning for resilience, particularly when port and city authorities pursue the same strategies. In view of contemporary challenges, this special section demonstrates the value of further research on port city resilience and vulnerability. The section raises an important question: Is it possible to balance the wide-ranging economic interests of port actors and their view of waters as sites for shipping with those of local actors concerned about water quality and ecosystems?
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- 2020
47. C.3 Gebaute Umwelt – Wohnen und Lebensstile Dirk Schubert
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Dirk Schubert
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- 2020
48. 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
49. Serotonergic development of active sensing
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Alireza Azarfar, Judith R. Homberg, Artoghrul Alishbayli, Tansu Celikel, Yiping Zhang, and Dirk Schubert
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Knockout rat ,biology ,Period (gene) ,biology.protein ,Motor control ,Transporter ,Sensory system ,Serotonin ,Serotonergic ,Neuroscience ,Serotonin transporter - Abstract
Active sensing requires adaptive motor (positional) control of sensory organs based on contextual, sensory and task requirements, and develops postnatally after the maturation of intracortical circuits. Alterations in sensorimotor network connectivity during this period are likely to impact sensorimotor computation also in adulthood. Serotonin is among the cardinal developmental regulators of network formation, thus changing the serotonergic drive might have consequences for the emergence and maturation of sensorimotor control. Here we tested this hypothesis on an object localization task by quantifying the motor control dynamics of whiskers during tactile navigation. The results showed that sustained alterations in serotonergic signaling in serotonin transporter knockout rats, or the transient pharmacological inactivation of the transporter during early postnatal development, impairs the emergence of adaptive motor control of whisker position based on recent sensory information. A direct outcome of this altered motor control is that the mechanical force transmitted to whisker follicles upon contact is reduced, suggesting that increased excitability observed upon altered serotonergic signaling is not due to increased synaptic drive originating from the periphery upon whisker contact. These results argue that postnatal development of adaptive motor control requires intact serotonergic signaling and that even its transient dysregulation during early postnatal development causes lasting sensorimotor impairments in adulthood.
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- 2019
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50. Brunner Syndrome associated MAOA dysfunction in human induced dopaminergic neurons results in dysregulated NMDAR expression and increased network activity
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Dirk Schubert, Barbara Franke, Sarah Kittel-Schneider, Maren Bormann, Marina Hakobjan, J.R. van Rhijn, Britt Mossink, Yingjie Shi, Nael Nadif Kasri, Han G. Brunner, and Monica Frega
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biology ,Brunner syndrome ,Dopaminergic ,Neurotransmission ,Serotonergic ,medicine.disease ,Monoamine neurotransmitter ,Dopamine ,biology.protein ,medicine ,Serotonin ,Monoamine oxidase A ,Neuroscience ,medicine.drug - Abstract
Monoamine oxidase A (MAOA) is an enzyme that catalyzes the degradation of dopamine, noradrenaline, and serotonin. Regulation of monoamine neurotransmitter abundance through MAOA activity strongly affects motor control, emotion, and cognitive function. Mutations in MAOA cause Brunner Syndrome, which is characterized by impulsive aggressive behavior and mild intellectual disability (ID). The impaired MAOA activity in Brunner Syndrome patients results in bioamine aberration, but it is currently unknown how this affects neuronal function. MAOA is highly expressed in serotonergic and dopaminergic neurons, and dysfunction of both neurotransmission systems is associated with aggressive behavior in mice and humans. Research has so far mainly focused on the serotonergic system. Here, we generated human induced pluripotent stem cell-derived induced dopaminergic neurons (iDANs) from individuals with known MAOA mutations, to investigate MAOA-dependent effects on dopamine neuronal function in the context of Brunner Syndrome. We assessed iDAN lines from three patients and combined data from morphological analysis, gene expression, single-cell electrophysiology, and network analysis using micro-electrode arrays (MEAs). We observed mutation-dependent functional effects as well as overlapping changes in iDAN morphology. The most striking effect was a clear increase in N-methyl-D-aspartate (NMDA) receptor mRNA expression in all patient lines. A marked increase was also seen in coordinated network activity (network bursts) on the MEA in all patient lines, while single-cell intrinsic properties and spontaneous excitatory postsynaptic currents activity appeared normal. Together, our data indicate that dysfunction of MAOA leads to increased coordinated network activity in iDANs, possibly caused by increased synaptic NMDA receptor expression.
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- 2019
- Full Text
- View/download PDF
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