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  • American Association for the Advancement of Science (AAAS)  (1)
  • American Meteorological Society  (1)
  • 1
    Publication Date: 2019
    Description: 〈p〉Disruptions in the ubiquitin protein ligase E3A (〈i〉UBE3A〈/i〉) gene cause Angelman syndrome (AS). Whereas AS model mice have associated synaptic dysfunction and altered plasticity with abnormal behavior, whether similar or other mechanisms contribute to network hyperactivity and epilepsy susceptibility in AS patients remains unclear. Using human neurons and brain organoids, we demonstrate that UBE3A suppresses neuronal hyperexcitability via ubiquitin-mediated degradation of calcium- and voltage-dependent big potassium (BK) channels. We provide evidence that augmented BK channel activity manifests as increased intrinsic excitability in individual neurons and subsequent network synchronization. BK antagonists normalized neuronal excitability in both human and mouse neurons and ameliorated seizure susceptibility in an AS mouse model. Our findings suggest that BK channelopathy underlies epilepsy in AS and support the use of human cells to model human developmental diseases.〈/p〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2008-02-01
    Description: This study represents the first attempt at developing a comprehensive climatology of atmospheric and surface water and energy budgets for the Mackenzie River basin (MRB). Different observed, remotely sensed, (re)analyzed, and modeled datasets were used to obtain independent estimates of the budgets. In particular, assimilated datasets, including the National Centers for Environmental Prediction Global Reanalysis 2 (NCEP-R2), the global 40-yr European Centre for Medium-Range Weather Forecasts Re-Analysis (ERA-40), the NCEP North American Regional Reanalysis (NARR), and the Canadian Meteorological Centre (CMC) operational regional analysis as well as results from the Canadian Regional Climate Model (CRCM) simulations, are used in the study. Apart from the development of state-of-the-art budget estimates for the MRB, the relative merits of current models, data assimilation systems, and global blended datasets in representing aspects of the water and energy cycle of this northern and data-sparse region were also assessed. In addition, the levels of uncertainty in assessing the budgets as well as their sources are discussed. The regional water budget for the MRB is closed within 10% of the observed runoff by using the moisture flux convergence from ERA-40, NARR, CMC, or CRCM. While these are noted improvements over previous water closure assessments for the region, magnitudes of the residuals in balancing the budgets are often comparable to the budget terms themselves in all the model and analysis datasets, and the spreads of budget estimates from the different datasets are also typically large, suggesting that substantial improvements to the models and observations are needed before the assessments of water and energy budgets for this northern region can be vastly improved.
    Print ISSN: 1525-755X
    Electronic ISSN: 1525-7541
    Topics: Geography , Geosciences , Physics
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