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"Clark, Sarah"
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Cryo-EM structures reveal native GABAA receptor assemblies and pharmacology
Type A γ-aminobutyric acid receptors (GABA
A
Rs) are the principal inhibitory receptors in the brain and the target of a wide range of clinical agents, including anaesthetics, sedatives, hypnotics and antidepressants
1
–
3
. However, our understanding of GABA
A
R pharmacology has been hindered by the vast number of pentameric assemblies that can be derived from 19 different subunits
4
and the lack of structural knowledge of clinically relevant receptors. Here, we isolate native murine GABA
A
R assemblies containing the widely expressed α1 subunit and elucidate their structures in complex with drugs used to treat insomnia (zolpidem (ZOL) and flurazepam) and postpartum depression (the neurosteroid allopregnanolone (APG)). Using cryo-electron microscopy (cryo-EM) analysis and single-molecule photobleaching experiments, we uncover three major structural populations in the brain: the canonical α1β2γ2 receptor containing two α1 subunits, and two assemblies containing one α1 and either an α2 or α3 subunit, in which the single α1-containing receptors feature a more compact arrangement between the transmembrane and extracellular domains. Interestingly, APG is bound at the transmembrane α/β subunit interface, even when not added to the sample, revealing an important role for endogenous neurosteroids in modulating native GABA
A
Rs. Together with structurally engaged lipids, neurosteroids produce global conformational changes throughout the receptor that modify the ion channel pore and the binding sites for GABA and insomnia medications. Our data reveal the major α1-containing GABA
A
R assemblies, bound with endogenous neurosteroid, thus defining a structural landscape from which subtype-specific drugs can be developed.
Using cryo-EM, structures of three major assemblies of type A GABA receptors, which regulate brain excitability, are revealed in the mouse brain and provide a basis for the development of subtype-specific drugs.
Journal Article
The Complexities of Navigating the Healthcare System as an Autistic Individual with Ehlers-Danlos Syndrome: A Patient Perspective
Autistic individuals with hypermobile Ehlers-Danlos syndrome (hEDS) often face unique challenges navigating healthcare systems due to lack of clinician awareness, diagnostic delays, misdiagnoses, and systemic barriers. Drawing on my own lived experience within the UK's National Health Service (NHS), this patient perspective article integrates personal narratives with the research and literature, highlighting critical gaps in clinical care, offering practical recommendations to enhance equity and inclusion. Recommendations include: improved clinician education on neurodivergence and overlapping conditions, improving holistic patient-centred communication, and collaborative care models that prioritise patient needs, learning from lived expertise.
Journal Article
The origins of happiness : the science of well-being over the life course
\"What makes people happy? Why should governments care about people's well-being? How would policy change if well-being was the main objective? The Origins of Happiness seeks to revolutionize how we think about human priorities and to promote public policy changes that are based on what really matters to people. Drawing on a uniquely comprehensive range of evidence from longitudinal data on over one hundred thousand individuals in Britain, the United States, Australia, and Germany, the authors consider the key factors that affect human well-being. The authors explore factors such as income, education, employment, family conflict, health, childcare, and crime -- and their findings are not what we might expect. Contrary to received wisdom, income inequality accounts for only two percent or less of the variance in happiness across the population; the critical factors affecting a person's happiness are their relationships and their mental and physical health. More people are in misery due to mental illness than to poverty, unemployment, or physical illness. Examining how childhood influences happiness in adulthood, the authors show that academic performance is a less important predictor than emotional health and behavior, which is shaped tremendously by schools, individual teachers, and parents. For policymakers, the authors propose new forms of cost-effectiveness analysis that places well-being at center stage. Groundbreaking in its scope and results, The Origins of Happiness offers all of us a new vision for how we might become more healthy, happy, and whole\"-- Provided by publisher.
Book
Airway Prevotella promote TLR2-dependent neutrophil activation and rapid clearance of Streptococcus pneumoniae from the lung
This study investigates how specific members of the lung microbiome influence the early immune response to infection.
Prevotella
species are a major component of the endogenous airway microbiota. Increased abundance of
Prevotella melaninogenica
correlates with reduced infection with the bacterial pathogen
Streptococcus pneumoniae
, indicating a potentially beneficial role. Here, we show that
P. melaninogenica
enhances protection against
S. pneumoniae
, resulting in rapid pathogen clearance from the lung and improved survival in a mouse lung co-infection model. This response requires recognition of
P. melaninogenica
lipoproteins by toll-like receptor (TLR)2, the induction of TNFα, and neutrophils, as the loss of any of these factors abrogates
Prevotella
-induced protection. Improved clearance of
S. pneumoniae
is associated with increased serine protease-mediated killing by lung neutrophils and restraint of
P. melaninogenica
-induced inflammation by IL-10 in co-infected mice. Together, these findings highlight innate immune priming by airway
Prevotella
as an important protective feature in the respiratory tract.
How the airway microbiome protects against bacterial pneumonia remains unclear. Here, the authors identify airway bacterial species that activate the immune system to facilitate rapid clearance of the pathogen
Streptococcus pneumoniae
from the lung.
Journal Article
Art's biggest stage : collecting the Venice Bienniale, 2007-2019
\"The Clark Library has a collection of publications and ephemera relating to the Venice Biennale that dates back to the event's beginning in 1895. Art's Biggest Stage: Collecting the Venice Biennale, 2007-2019 is the first deep dive into the library's various holdings related to the event. Drawing primarily from our collection of publications and ephemera, this book emphasizes notions of nationhood while at the same time evoking the spectacle of the Biennale itself\"-- Provided by publisher.
Book
Hippocampal AMPA receptor assemblies and mechanism of allosteric inhibition
AMPA-selective glutamate receptors mediate the transduction of signals between the neuronal circuits of the hippocampus
1
. The trafficking, localization, kinetics and pharmacology of AMPA receptors are tuned by an ensemble of auxiliary protein subunits, which are integral membrane proteins that associate with the receptor to yield bona fide receptor signalling complexes
2
. Thus far, extensive studies of recombinant AMPA receptor–auxiliary subunit complexes using engineered protein constructs have not been able to faithfully elucidate the molecular architecture of hippocampal AMPA receptor complexes. Here we obtain mouse hippocampal, calcium-impermeable AMPA receptor complexes using immunoaffinity purification and use single-molecule fluorescence and cryo-electron microscopy experiments to elucidate three major AMPA receptor–auxiliary subunit complexes. The GluA1–GluA2, GluA1–GluA2–GluA3 and GluA2–GluA3 receptors are the predominant assemblies, with the auxiliary subunits TARP-γ8 and CNIH2–SynDIG4 non-stochastically positioned at the B′/D′ and A′/C′ positions, respectively. We further demonstrate how the receptor–TARP-γ8 stoichiometry explains the mechanism of and submaximal inhibition by a clinically relevant, brain-region-specific allosteric inhibitor.
Analyses of hippocampal AMPA receptor–auxiliary subunit complexes provide insights into the predominant assemblies and organization of the AMPA receptor, TARP-γ8 and CNIH2/SynDIG4 and explain the mechanism of inhibition of a clinically relevant, brain-region-specific allosteric inhibitor.
Journal Article
Structures of the TMC-1 complex illuminate mechanosensory transduction
The initial step in the sensory transduction pathway underpinning hearing and balance in mammals involves the conversion of force into the gating of a mechanosensory transduction channel
1
. Despite the profound socioeconomic impacts of hearing disorders and the fundamental biological significance of understanding mechanosensory transduction, the composition, structure and mechanism of the mechanosensory transduction complex have remained poorly characterized. Here we report the single-particle cryo-electron microscopy structure of the native transmembrane channel-like protein 1 (TMC-1) mechanosensory transduction complex isolated from
Caenorhabditis elegans
. The two-fold symmetric complex is composed of two copies each of the pore-forming TMC-1 subunit, the calcium-binding protein CALM-1 and the transmembrane inner ear protein TMIE. CALM-1 makes extensive contacts with the cytoplasmic face of the TMC-1 subunits, whereas the single-pass TMIE subunits reside on the periphery of the complex, poised like the handles of an accordion. A subset of complexes additionally includes a single arrestin-like protein, arrestin domain protein (ARRD-6), bound to a CALM-1 subunit. Single-particle reconstructions and molecular dynamics simulations show how the mechanosensory transduction complex deforms the membrane bilayer and suggest crucial roles for lipid–protein interactions in the mechanism by which mechanical force is transduced to ion channel gating.
Structural studies of the native transmembrane channel-like protein 1 (TMC-1) mechanosensory transduction channel complex of
Caenorhabditis elegans
reveal the subunit composition and the roles of protein–membrane interactions in the conversion of mechanical force to ion channel activity.
Journal Article
Basal autophagy is required for promoting dendritic terminal branching in Drosophila sensory neurons
Dendrites function as the primary sites for synaptic input and integration with impairments in dendritic arborization being associated with dysfunctional neuronal circuitry. Post-mitotic neurons require high levels of basal autophagy to clear cytotoxic materials and autophagic dysfunction under native or cellular stress conditions has been linked to neuronal cell death as well as axo-dendritic degeneration. However, relatively little is known regarding the developmental role of basal autophagy in directing aspects of dendritic arborization or the mechanisms by which the autophagic machinery may be transcriptionally regulated to promote dendritic diversification. We demonstrate that autophagy-related (Atg) genes are positively regulated by the homeodomain transcription factor Cut, and that basal autophagy functions as a downstream effector pathway for Cut-mediated dendritic terminal branching in Drosophila multidendritic (md) sensory neurons. Further, loss of function analyses implicate Atg genes in promoting cell type-specific dendritic arborization and terminal branching, while gain of function studies suggest that excessive autophagy leads to dramatic reductions in dendritic complexity. We demonstrate that the Atg1 initiator kinase interacts with the dual leucine zipper kinase (DLK) pathway by negatively regulating the E3 ubiquitin ligase Highwire and positively regulating the MAPKKK Wallenda. Finally, autophagic induction partially rescues dendritic atrophy defects observed in a model of polyglutamine toxicity. Collectively, these studies implicate transcriptional control of basal autophagy in directing dendritic terminal branching and demonstrate the importance of homeostatic control of autophagic levels for dendritic arbor complexity under native or cellular stress conditions.
Journal Article