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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.
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Discovery of Tricyclic Indoles That Potently Inhibit Mcl-1 Using Fragment-Based Methods and Structure-Based Design
Abstract not provided
Thermodynamic and Structure Guided Design of Statin Based Inhibitors of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase
Abstract not provided
Structure-Based Design of Irreversible Human KAT II Inhibitors: Discovery of New Potency-Enhancing I
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Structure-Based Design and Synthesis of an HIV-1 Entry Inhibitor Exploiting X-ray and Thermodynamic Characterization
Abstract not provided
Generation of bispecific IgG antibodies by structure-based design of an orthogonal Fab interface
Abstract not provided
Structure-guided design of an Hsp90β N-terminal isoform-selective inhibitor
Abstract not provided
Inhibiting amyloid-β cytotoxicity through its interaction with the cell surface receptor LilrB2 by structure-based design
Abstract not provided
Binding site elucidation and structure guided design of macrocyclic IL-17A antagonists
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A novel P3-type Na2/3Mg1/3Mn2/3O2 as high capacity sodium-ion cathode using reversible oxygen redox
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Structure-based design of haloperidol analogues as inhibitors of acetyltransferase Eis from Mycobact
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Electromagnetic analysis of a wind turbine magnetic gearbox
The design of the second stage of a 59:1 multi‐stage magnetic gearbox for a wind turbine demonstrator is presented. The multi‐stage series‐connected magnetic gearbox is composed of a 6.45 first stage and 9.14 second stage. A flux‐focusing spoke‐type rotor typology is used with a unique segmented fully laminated design. The impact of structural design changes is considered with respect to torque density. A new rotor typology is presented that enables the magnetic gearbox to be mechanically assembled first without magnets.
Structure-based design and mechanisms of allosteric inhibitors for mitochondrial branched-chain [alpha]-ketoacid dehydrogenase kinase
Abstract not provided
Structure-based design of nanobodies that inhibit seeding of Alzheimer’s patient–extracted tau fibrils
Despite much effort, antibody therapies for Alzheimer’s disease (AD) have shown limited efficacy. Challenges to the rational design of effective antibodies include the difficulty of achieving specific affinity to critical targets, poor expression, and antibody aggregation caused by buried charges and unstructured loops. To overcome these challenges, we grafted previously determined sequences of fibril-capping amyloid inhibitors onto a camel heavy chain antibody scaffold. These sequences were designed to cap fibrils of tau, known to form the neurofibrillary tangles of AD, thereby preventing fibril elongation. The nanobodies grafted with capping inhibitors blocked tau aggregation in biosensor cells seeded with postmortem brain extracts from AD and progressive supranuclear palsy (PSP) patients. The tau capping nanobody inhibitors also blocked seeding by recombinant tau oligomers. Another challenge to the design of effective antibodies is their poor blood–brain barrier (BBB) penetration. In this study, we also designed a bispecific nanobody composed of a nanobody that targets a receptor on the BBB and a tau capping nanobody inhibitor, conjoined by a flexible linker. We provide evidence that the bispecific nanobody improved BBB penetration over the tau capping inhibitor alone after intravenous administration in mice. Our results suggest that the design of synthetic antibodies that target sequences that drive protein aggregation may be a promising approach to inhibit the prion-like seeding of tau and other proteins involved in AD and related proteinopathies.
Design and structural basis of selective 1,4-dihydropyridine inhibitors of the calcium-activated potassium channel K Ca 3.1
The 1,4-dihydropyridines, drugs with well-established bioavailability and toxicity profiles, have proven efficacy in treating human hypertension, peripheral vascular disorders, and coronary artery disease. Every 1,4-dihydropyridine in clinical use blocks L-type voltage-gated calcium channels. We now report our development, using selective optimization of a side activity (SOSA), of a class of 1,4-dihydropyridines that selectively and potently inhibit the intermediate-conductance calcium-activated K + channel K Ca 3.1, a validated therapeutic target for diseases affecting many organ systems. One of these 1,4-dihydropyridines, DHP-103, blocked K Ca 3.1 with an IC 50 of 6 nM and exhibited exquisite selectivity over calcium channels and a panel of >100 additional molecular targets. Using high-resolution structure determination by cryogenic electron microscopy together with mutagenesis and electrophysiology, we delineated the drug binding pocket for DHP-103 within the water-filled central cavity of the K Ca 3.1 channel pore, where bound drug directly impedes ion permeation. DHP-103 inhibited gain-of-function mutant K Ca 3.1 channels that cause hereditary xerocytosis, suggesting its potential use as a therapeutic for this hemolytic anemia. In a rat model of acute ischemic stroke, the second leading cause of death worldwide, DHP-103 administered 12 h postischemic insult in proof-of-concept studies reduced infarct volume, improved balance beam performance (measure of proprioception) and decreased numbers of activated microglia in infarcted areas. K Ca 3.1-selective 1,4-dihydropyridines hold promise for the many diseases for which K Ca 3.1 has been experimentally confirmed as a therapeutic target.
Combining random mutagenesis, structure-guided design and next-generation sequencing to mitigate pol
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Acceleration of heavy ions in inverse free electron laser
In conventional linear accelerators, the beam is accelerated with a synchronous harmonic of the radio frequency field where the electric field component is collinear with the beam direction. This approach requires the design of complex accelerating structures, especially for low-energy heavy ions. If the beam motion were sustainably coupled to transverse electromagnetic fields, this could significantly simplify the accelerating structure design, and even allow acceleration with free-space waves. However, despite the long history of the proposed concept for accelerating low-velocity ion beams, it has not found practical application, partially because of the complexity of the technical design. In this paper, we present a practical design approach for this undulator-based accelerator for low-energy heavy-ions, reminiscent of the inverse free electron laser operating principle, but in a different parameter space.