| 21. |
- Cowgill, John, et al.
(författare)
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Structure and dynamics of differential ligand binding in the human ρ-type GABAA receptor
- 2023
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Ingår i: Neuron. - : Elsevier BV. - 0896-6273 .- 1097-4199. ; 111:21, s. 5-3450
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Tidskriftsartikel (refereegranskat)abstract
- The neurotransmitter γ-aminobutyric acid (GABA) drives critical inhibitory processes in and beyond the nervous system, partly via ionotropic type-A receptors (GABAARs). Pharmacological properties of ρ-type GABAARs are particularly distinctive, yet the structural basis for their specialization remains unclear. Here, we present cryo-EM structures of a lipid-embedded human ρ1 GABAAR, including a partial intracellular domain, under apo, inhibited, and desensitized conditions. An apparent resting state, determined first in the absence of modulators, was recapitulated with the specific inhibitor (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid and blocker picrotoxin and provided a rationale for bicuculline insensitivity. Comparative structures, mutant recordings, and molecular simulations with and without GABA further explained the sensitized but slower activation of ρ1 relative to canonical subtypes. Combining GABA with picrotoxin also captured an apparent uncoupled intermediate state. This work reveals structural mechanisms of gating and modulation with applications to ρ-specific pharmaceutical design and to our biophysical understanding of ligand-gated ion channels.
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| 22. |
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| 23. |
- Delegates, Global Neuroethics Summit, et al.
(författare)
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Neuroethics Questions to Guide Ethical Research in the International Brain Initiatives
- 2018
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Ingår i: Neuron. - : CELL PRESS. - 0896-6273 .- 1097-4199. ; 100:1, s. 19-36
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Forskningsöversikt (refereegranskat)abstract
- Increasingly, national governments across the globe are prioritizing investments in neuroscience. Currently, seven active or in-development national-level brain research initiatives exist, spanning four continents. Engaging with the underlying values and ethical concerns that drive brain research across cultural and continental divides is critical to future research. Culture influences what kinds of science are supported and where science can be conducted through ethical frameworks and evaluations of risk. Neuroscientists and philosophers alike have found themselves together encountering perennial questions; these questions are engaged by the field of neuroethics, related to the nature of understanding the self and identity, the existence and meaning of free will, defining the role of reason in human behavior, and more. With this Perspective article, we aim to prioritize and advance to the foreground a list of neuroethics questions for neuroscientists operating in the context of these international brain initiatives.
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| 24. |
- Dewan, Ramita, et al.
(författare)
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Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.
- 2021
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Ingår i: Neuron. - : Elsevier BV. - 1097-4199 .- 0896-6273. ; 109:3
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Tidskriftsartikel (refereegranskat)abstract
- We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.
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| 29. |
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| 30. |
- Dudai, Yadin, et al.
(författare)
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To simulate or not to simulate : What are the questions?
- 2014
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Ingår i: Neuron. - : Elsevier BV. - 0896-6273 .- 1097-4199. ; 84:2, s. 254-261
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Forskningsöversikt (refereegranskat)abstract
- Simulation is a powerful method in science and engineering. However, simulation is an umbrella term, and its meaning and goals differ among disciplines. Rapid advances in neuroscience and computing draw increasing attention to large-scale brain simulations. What is the meaning of simulation, and what should the method expect to achieve? We discuss the concept of simulation from an integrated scientific and philosophical vantage point and pinpoint selected issues that are specific to brain simulation.
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