A5091206413- Myasthenia Gravis and Thymoma
- Ion channel regulation and function
- Autoimmune Neurological Disorders and Treatments
- Cellular transport and secretion
- Neuroscience and Neuropharmacology Research
- Cell Image Analysis Techniques
- Advanced Fluorescence Microscopy Techniques
- Neuroscience and Neural Engineering
- Advanced Electron Microscopy Techniques and Applications
- Cancer Treatment and Pharmacology
- Topological and Geometric Data Analysis
- Botulinum Toxin and Related Neurological Disorders
- Cancer therapeutics and mechanisms
- Peripheral Neuropathies and Disorders
- Synthesis and Biological Evaluation
- Alzheimer's disease research and treatments
- Lipid Membrane Structure and Behavior
University of Pittsburgh
2012-2024
University of Maryland, Baltimore
2020-2022
John Wiley & Sons (United States)
2018
New York Academy of Sciences
2018
Hudson Institute
2018
Center for the Neural Basis of Cognition
2012-2014
We developed a novel calcium (Ca<sup>2+</sup>) channel agonist that is selective for N- and P/Q-type Ca<sup>2+</sup> channels, which are the channels regulate transmitter release at most synapses. have shown this new molecule (GV-58) slows deactivation of resulting in large increase presynaptic entry during activity. GV-58 was as modification (<i>R</i>)-roscovitine, previously to be agonist, addition its known cyclin-dependent kinase In comparison with parent molecule, has ∼20-fold less...
We have investigated the impact of transmitter release site (active zone; AZ) structure on synaptic function by physically rearranging individual AZ elements in a previously published frog neuromuscular junction (NMJ) model into organization observed mouse NMJ AZ. used this strategy, purposefully without changing properties between and models (even though there are undoubtedly differences vivo), to directly test how influences at level an Despite similarly ordered ion channel array...
Key points Lambert–Eaton myasthenic syndrome (LEMS) is characterized by an autoimmune‐mediated attack on presynaptic P/Q‐type Ca 2+ channels at the neuromuscular junction (NMJ). The current common symptomatic treatment option 3,4‐diaminopyridine (3,4‐DAP), a potassium channel blocker that widens action potential, causing increase in amount of neurotransmitter release. This approach, however, does not completely reverse symptoms and can have dose‐limiting side‐effects. Thus, there need for...
Abstract Cells and tissues are made out of nanoscale building blocks, such as proteins, organized in crowded nanostructures. We show that many biomolecules, the nanostructures which they embedded, may be invisible to prior imaging techniques, due inaccessibility labels (e.g., antibodies) biomolecules embedded within structures. developed a technology, expansion revealing (ExR), isotropically decrowds proteins from each other, enable their labeling. use ExR discover alignment presynaptic...
The acute effect of the potent cyclin-dependent kinase (cdk) inhibitor (R)-roscovitine on Ca2+ channels inspired development structural analogues as a potential treatment for motor nerve terminal dysfunction. On basis versatile chlorinated purine scaffold, we have synthesized ca. 20 derivatives and characterized their N-type channel agonist action. Agents that showed strong effects were also in panel off-target effects. Among several novel compounds with diminished cdk activity, identified...
Proteins work together in nanostructures many physiological contexts and disease states. We recently developed expansion revealing (ExR), which expands proteins away from each other, order to support better labeling with antibody tags nanoscale imaging on conventional microscopes. Here, we report multiplexed (multiExR), enables high-fidelity visualization of >20 the same specimen, over serial rounds staining imaging. Across all datasets examined, multiExR exhibits a median round-to-round...
Lambert-Eaton myasthenic syndrome (LEMS) causes neuromuscular weakness as a result of an autoimmune attack on the calcium channels that normally regulate chemical transmitter release at junction. Currently there are limited treatment options for patients with this and other forms weakness. A novel, first-in-class channel agonist is selective types voltage-gated synapses has recently been developed. This compound (GV-58) slows deactivation (closing) channel, resulting in large increase total...
Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune-mediated neuromuscular disease thought to be caused by autoantibodies against P/Q-type voltage-gated calcium channels (VGCCs), which attack and reduce the number of VGCCs within transmitter release sites (active zones; AZs) at junction (NMJ), resulting in weakness. However, patients with LEMS also have antibodies other neuronal proteins, about 15% are seronegative for VGCCs. We hypothesized that a reduction alone not sufficient...