@article{14841, abstract = {De novo heterozygous variants in KCNC2 encoding the voltage-gated potassium (K+) channel subunit Kv3.2 are a recently described cause of developmental and epileptic encephalopathy (DEE). A de novo variant in KCNC2 c.374G > A (p.Cys125Tyr) was identified via exome sequencing in a patient with DEE. Relative to wild-type Kv3.2, Kv3.2-p.Cys125Tyr induces K+ currents exhibiting a large hyperpolarizing shift in the voltage dependence of activation, accelerated activation, and delayed deactivation consistent with a relative stabilization of the open conformation, along with increased current density. Leveraging the cryogenic electron microscopy (cryo-EM) structure of Kv3.1, molecular dynamic simulations suggest that a strong π-π stacking interaction between the variant Tyr125 and Tyr156 in the α-6 helix of the T1 domain promotes a relative stabilization of the open conformation of the channel, which underlies the observed gain of function. A multicompartment computational model of a Kv3-expressing parvalbumin-positive cerebral cortex fast-spiking γ-aminobutyric acidergic (GABAergic) interneuron (PV-IN) demonstrates how the Kv3.2-Cys125Tyr variant impairs neuronal excitability and dysregulates inhibition in cerebral cortex circuits to explain the resulting epilepsy.}, author = {Clatot, Jerome and Currin, Christopher and Liang, Qiansheng and Pipatpolkai, Tanadet and Massey, Shavonne L. and Helbig, Ingo and Delemotte, Lucie and Vogels, Tim P and Covarrubias, Manuel and Goldberg, Ethan M.}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, number = {3}, publisher = {Proceedings of the National Academy of Sciences}, title = {{A structurally precise mechanism links an epilepsy-associated KCNC2 potassium channel mutation to interneuron dysfunction}}, doi = {10.1073/pnas.2307776121}, volume = {121}, year = {2024}, } @inproceedings{14993, abstract = {Traditional top-down approaches for global health have historically failed to achieve social progress (Hoffman et al., 2015; Hoffman & Røttingen, 2015). Recently, however, a more holistic, multi-level approach termed One Health (OH) (Osterhaus et al., 2020) is being adopted. Several sets of challenges have been identified for the implementation of OH (dos S. Ribeiro et al., 2019), including policy and funding, education and training, and multi-actor, multi-domain, and multi-level collaborations. These exist despite the increasing accessibility to knowledge and digital collaborative research tools through the internet. To address some of these challenges, we propose a general framework for grassroots community-based means of participatory research. Additionally, we present a specific roadmap to create a Machine Learning for Global Health community in Africa. The proposed framework aims to enable any small group of individuals with scarce resources to build and sustain an online community within approximately two years. We provide a discussion on the potential impact of the proposed framework for global health research collaborations.}, author = {Currin, Christopher and Asiedu , Mercy Nyamewaa and Fourie, Chris and Rosman, Benjamin and Turki, Houcemeddine and Lambebo Tonja, Atnafu and Abbott, Jade and Ajala, Marvellous and Adedayo, Sadiq Adewale and Emezue, Chris Chinenye and Machangara, Daphne}, booktitle = {1st Workshop on Machine Learning & Global Health}, location = {Kigali, Rwanda}, publisher = {OpenReview}, title = {{A framework for grassroots research collaboration in machine learning and global health}}, year = {2023}, } @inbook{12866, abstract = {Autism spectrum disorder (ASD) and epilepsy are frequently comorbid neurodevelopmental disorders. Extensive research has demonstrated shared pathological pathways, etiologies, and phenotypes. Many risk factors for these disorders, like genetic mutations and environmental pressures, are linked to changes in childhood brain development, which is a critical period for their manifestation. Decades of research have yielded many signatures for ASD and epilepsy, some shared and others unique or opposing. The anatomical, physiological, and behavioral correlates of these disorders are discussed in this chapter in the context of understanding shared pathological pathways. We end with important takeaways on the presentation, prevention, intervention, and policy changes for ASD and epilepsy. This chapter aims to explore the complexity of these disorders, both in etiology and phenotypes, with the further goal of appreciating the expanse of unknowns still to explore about the brain.}, author = {Currin, Christopher and Beyer, Chad}, booktitle = {Encyclopedia of Child and Adolescent Health}, editor = {Halpern-Felsher, Bonnie}, isbn = {9780128188736}, pages = {86--98}, publisher = {Elsevier}, title = {{Altered childhood brain development in autism and epilepsy}}, doi = {10.1016/b978-0-12-818872-9.00129-1}, year = {2023}, } @article{11143, abstract = {Dravet syndrome is a neurodevelopmental disorder characterized by epilepsy, intellectual disability, and sudden death due to pathogenic variants in SCN1A with loss of function of the sodium channel subunit Nav1.1. Nav1.1-expressing parvalbumin GABAergic interneurons (PV-INs) from young Scn1a+/− mice show impaired action potential generation. An approach assessing PV-IN function in the same mice at two time points shows impaired spike generation in all Scn1a+/− mice at postnatal days (P) 16–21, whether deceased prior or surviving to P35, with normalization by P35 in surviving mice. However, PV-IN synaptic transmission is dysfunctional in young Scn1a+/− mice that did not survive and in Scn1a+/− mice ≥ P35. Modeling confirms that PV-IN axonal propagation is more sensitive to decreased sodium conductance than spike generation. These results demonstrate dynamic dysfunction in Dravet syndrome: combined abnormalities of PV-IN spike generation and propagation drives early disease severity, while ongoing dysfunction of synaptic transmission contributes to chronic pathology.}, author = {Kaneko, Keisuke and Currin, Christopher and Goff, Kevin M. and Wengert, Eric R. and Somarowthu, Ala and Vogels, Tim P and Goldberg, Ethan M.}, issn = {2211-1247}, journal = {Cell Reports}, number = {13}, publisher = {Elsevier}, title = {{Developmentally regulated impairment of parvalbumin interneuron synaptic transmission in an experimental model of Dravet syndrome}}, doi = {10.1016/j.celrep.2022.110580}, volume = {38}, year = {2022}, } @article{12225, abstract = {In social networks, users often engage with like-minded peers. This selective exposure to opinions might result in echo chambers, i.e., political fragmentation and social polarization of user interactions. When echo chambers form, opinions have a bimodal distribution with two peaks on opposite sides. In certain issues, where either extreme positions contain a degree of misinformation, neutral consensus is preferable for promoting discourse. In this paper, we use an opinion dynamics model that naturally forms echo chambers in order to find a feedback mechanism that bridges these communities and leads to a neutral consensus. We introduce the random dynamical nudge (RDN), which presents each agent with input from a random selection of other agents’ opinions and does not require surveillance of every person’s opinions. Our computational results in two different models suggest that the RDN leads to a unimodal distribution of opinions centered around the neutral consensus. Furthermore, the RDN is effective both for preventing the formation of echo chambers and also for depolarizing existing echo chambers. Due to the simple and robust nature of the RDN, social media networks might be able to implement a version of this self-feedback mechanism, when appropriate, to prevent the segregation of online communities on complex social issues.}, author = {Currin, Christopher and Vera, Sebastián Vallejo and Khaledi-Nasab, Ali}, issn = {2045-2322}, journal = {Scientific Reports}, keywords = {Multidisciplinary}, publisher = {Springer Nature}, title = {{Depolarization of echo chambers by random dynamical nudge}}, doi = {10.1038/s41598-022-12494-w}, volume = {12}, year = {2022}, }