5 research outputs found
Identification of Neural Circuits by Imaging Coherent Electrical Activity with FRET-Based Dyes
AbstractWe show that neurons that underlie rhythmic patterns of electrical output may be identified by optical imaging and frequency-domain analysis. Our contrast agent is a two-component dye system in which changes in membrane potential modulate the relative emission between a pair of fluorophores. We demonstrate our methods with the circuit responsible for fictive swimming in the isolated leech nerve cord. The output of a motor neuron provides a reference signal for the phase-sensitive detection of changes in fluorescence from individual neurons in a ganglion. We identify known and possibly novel neurons that participate in the swim rhythm and determine their phases within a cycle. A variant of this approach is used to identify the postsynaptic followers of intracellularly stimulated neurons
An introductory biology lab that uses enzyme histochemistry to teach students about skeletal muscle fiber types
5,6-Dihydropyran-2-ones Possessing Various Sulfonyl Functionalities:Â Potent Nonpeptidic Inhibitors of HIV Protease
Discovery of Clinical Candidate 1‑{[(2<i>S</i>,3<i>S</i>,4<i>S</i>)‑3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin‑1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design
Through
fragment-based drug design focused on engaging the active
site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient
manner, a micromolar hit identified from a screen of a Pfizer fragment
library was optimized to afford IRAK4 inhibitors with nanomolar potency
in cellular assays. The medicinal chemistry effort featured the judicious
placement of lipophilicity, informed by co-crystal structures with
IRAK4 and optimization of ADME properties to deliver clinical candidate
PF-06650833 (compound <b>40</b>). This compound displays a 5-unit
increase in lipophilic efficiency from the fragment hit, excellent
kinase selectivity, and pharmacokinetic properties suitable for oral
administration