ORCID Profile
0000-0002-3758-1297
Current Organisations
Erasmus MC
,
University of Leeds
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Publisher: Wiley
Date: 20-07-2012
DOI: 10.1002/AJMG.A.35535
Publisher: Oxford University Press (OUP)
Date: 19-02-2021
DOI: 10.1093/HMG/DDAB050
Abstract: Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by deletion (~75%) or mutation (~10%) of the ubiquitin E3 ligase A (UBE3A) gene, which encodes a HECT type E3 ubiquitin protein ligase. Although the critical substrates of UBE3A are unknown, previous studies have suggested a critical role of nuclear UBE3A in AS pathophysiology. Here, we investigated to what extent UBE3A missense mutations disrupt UBE3A subcellular localization as well as catalytic activity, stability and protein folding. Our functional screen of 31 UBE3A missense mutants revealed that UBE3A mislocalization is the predominant cause of UBE3A dysfunction, accounting for 55% of the UBE3A mutations tested. The second major cause (29%) is a loss of E3-ubiquitin ligase activity, as assessed in an Escherichia coli in vivo ubiquitination assay. Mutations affecting catalytic activity are found not only in the catalytic HECT domain, but also in the N-terminal half of UBE3A, suggesting an important contribution of this N-terminal region to its catalytic potential. Together, our results show that loss of nuclear UBE3A E3 ligase activity is the predominant cause of UBE3A-linked AS. Moreover, our functional analysis screen allows rapid assessment of the pathogenicity of novel UBE3A missense variants which will be of particular importance when treatments for AS become available.
Publisher: Elsevier BV
Date: 2008
Publisher: Wiley
Date: 25-03-2019
DOI: 10.1002/AJMG.A.61125
Publisher: Wiley
Date: 25-03-2019
DOI: 10.1002/AJMG.A.61112
Publisher: Springer Science and Business Media LLC
Date: 24-03-2016
DOI: 10.1038/MP.2015.18
Abstract: Memories are encoded within sparsely distributed neuronal ensembles. However, the defining cellular properties of neurons within a memory trace remain incompletely understood. Using a fluorescence-based Arc reporter, we were able to visually identify the distinct subset of lateral amygdala (LA) neurons activated during auditory fear conditioning. We found that Arc- expressing neurons have enhanced intrinsic excitability and are preferentially recruited into newly encoded memory traces. Furthermore, synaptic potentiation of thalamic inputs to the LA during fear conditioning is learning-specific, postsynaptically mediated and highly localized to Arc -expressing neurons. Taken together, our findings validate the immediate-early gene Arc as a molecular marker for the LA neuronal ensemble recruited during fear learning. Moreover, these results establish a model of fear memory formation in which intrinsic excitability determines neuronal selection, whereas learning-related encoding is governed by synaptic plasticity.
Publisher: MDPI AG
Date: 08-02-2022
DOI: 10.3390/EN15031245
Abstract: An effective way to enhance the heat transfer in mini and micro electronic devices is to use different shapes of micro-channels containing vortex generators (VGs). This attracts researchers due to the reduced volume of the electronic micro-chips and increase in the heat generated from the devices. Another way to enhance the heat transfer is using nanofluids, which are considered to have great potential for heat transfer enhancement and are highly suited to application in practical heat transfer processes. Recently, several important studies have been carried out to understand and explain the causes of the enhancement or control of heat transfer using nanofluids. The main aim upon which the present work is based is to give a comprehensive review on the research progress on the heat transfer and fluid flow characteristics of nanofluids for both single- and two- phase models in different types of micro-channels. Both experimental and numerical studies have been reviewed for traditional and nanofluids in different types and shapes of micro-channels with vortex generators. It was found that the optimization of heat transfer enhancement should consider the pumping power reduction when evaluating the improvement of heat transfer.
Publisher: Elsevier BV
Date: 11-2018
Publisher: Springer Science and Business Media LLC
Date: 24-06-2019
DOI: 10.1038/S41593-019-0425-0
Abstract: Mutations affecting the gene encoding the ubiquitin ligase UBE3A cause Angelman syndrome. Although most studies focus on the synaptic function of UBE3A, we show that UBE3A is highly enriched in the nucleus of mouse and human neurons. We found that the two major isoforms of UBE3A exhibit highly distinct nuclear versus cytoplasmic subcellular localization. Both isoforms undergo nuclear import through direct binding to PSMD4 (also known as S5A or RPN10), but the amino terminus of the cytoplasmic isoform prevents nuclear retention. Mice lacking the nuclear UBE3A isoform recapitulate the behavioral and electrophysiological phenotypes of Ube3a
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Ype Elgersma.