Phosphodiesterases (PDEs) comprise a large family of enzymes that catalyze the hydrolysis of cAMP or cGMP and are implicated in various diseases. We describe the high-resolution crystal structures of the catalytic domains of PDE4B, PDE4D, and PDE5A with ten different inhibitors, including the drug candidates cilomilast and roflumilast, for respiratory diseases. These cocrystal structures reveal a common scheme of inhibitor binding to the PDEs: (i) a hydrophobic clamp formed by highly conserved hydrophobic residues that sandwich the inhibitor in the active site; (ii) hydrogen bonding to an invariant glutamine that controls the orientation of inhibitor binding. A scaffold can be readily identified for any given inhibitor based on the formation of these two types of conserved interactions. These structural insights will enable the design of isoform-selective inhibitors with improved binding affinity and should facilitate the discovery of more potent and selective PDE inhibitors for the treatment of a variety of diseases.
A triple-loop wireless power transmission (WPT) system equipped with closed-loop global power control, adaptive transmitter (Tx) resonance compensation (TRC), and automatic receiver (Rx) resonance tuning (ART) is presented. This system not only opposes coupling and load variations but also compensates for changes in the environment surrounding the inductive link to enhance power transfer efficiency (PTE) in applications such as implantable medical devices (IMDs). The Tx was built around a commercial off-the-shelf (COTS) radio-frequency identification (RFID) reader, operating at 13.56 MHz. A local Tx loop finds the optimal capacitance in parallel with the Tx coil by adjusting a varactor. A global power control loop maintains the received power at a desired level in the presence of changes in coupling distance, coil misalignments, and loading. Moreover, a local Rx loop is implemented inside a power management integrated circuit (PMIC) to avoid PTE degradation due to the Rx coil surrounding environment and process variations. The PMIC was fabricated in a 0.35- μm 4M2P standard CMOS process with 2.54 mm(2) active area. Measurement results show that the proposed triple-loop system improves the overall PTE by up to 10.5% and 4.7% compared to a similar open- and single closed-loop system, respectively, at nominal coil distance of 2 cm. The added TRC and ART loops contribute 2.3% and 1.4% to the overall PTE of 13.5%, respectively. This is the first WPT system to include three loops to dynamically compensate for environment and circuit variations and improve the overall power efficiency all the way from the driver output in Tx to the load in Rx.
[structure: see text] Oligothienyl-substituted paracyclophanes bearing alpha-thienyl substituents, which block polymerization at these sites, undergo oxidation to form stable radical cations and dications. Splitting of the first voltammetric oxidation wave of stacked dimers into two single-electron processes corresponding to formation of the stacked mono(radical cation) and the stacked bis(radical cation) illustrates the influence of pi-stacking on the behavior of conjugated chains, which serve as models for stacked polarons in conjugated polymers.
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