There have been speculations that the regulatory (R) subunit of the cAMP-dependent protein kinase (PKA) may have other functions. A recent study has shown that the catalytic (C) subunit of PKA may be regulated in a cAMP- and R subunit-independent manner. However, evidence linking a function to the R subunit apart from inhibiting the C subunit has been elusive. In this report, interaction cloning experiments showed that the RIalpha subunit association with the cytochrome c oxidase subunit Vb (CoxVb) is cAMP-sensitive. Interaction was detected with a GST-RIalpha fusion protein as well as by coimmunoprecipitation. Transient treatment with cAMP-elevating agents inhibited cytochrome c oxidase in Chinese hamster ovary (CHO) cells with a concomitant decrease in cytochrome c levels in the mitochondria and an increase in its release into the cytosol. Furthermore, mutant cells harboring a defective RIalpha show increased cytochrome c oxidase activity and also constitutively lower levels of cytochrome c in comparison to either the wild-type cells or the C subunit mutant. These results suggest a novel mechanism of cAMP signaling through the interaction of RIalpha with CoxVb thereby regulating cytochrome c oxidase activity as well as the cytochrome c levels.

We have analyzed a recently obtained crystal structure of human neuronal nitric oxide synthase (nNOS), then designed and synthesized several 2-aminopyridine derivatives containing a truncated side chain to avoid the hydrophobic pocket that differentiates human and rat nNOS in an attempt to explore alternative binding poses along the substrate access channel of human nNOS. Introduction of an N-methylethane-1,2-diamine side chain and conformational constraints such as benzonitrile and pyridine as the middle aromatic linker were sufficient to increase human and rat nNOS binding affinity and inducible and endothelial NOS selectivity. We found that 14b is a potent inhibitor; the binding modes with human and rat nNOS are unexpected, inducing side chain rotamer changes in Gln478 (rat) at the top of the active site. Compound 19c exhibits Ki values of 24 and 55 nM for rat and human nNOS, respectively, with 153-fold iNOS and 1040-fold eNOS selectivity. 19c has 18% oral bioavailability.

Nitrogen-doped carbon dots (CDs) have been produced by a new facile "bottom-up" synthesis, using the room-temperature reaction between acetonitrile and sodium-naphthalene. The obtained hydrophobic CDs are monodisperse (∼2.6 nm) and present an excitation-independent emission at ∼588 nm with a small full width at half-maximum (FWHM) of ∼52 nm. The CDs can be simply modified to be hydrosoluble and have been demonstrated to be an efficient red-emission agent for both in vivo and in vitro bioimaging.

One of the major challenges of daily wearable electroencephalogram (EEG) monitoring is that there are rarely suitable EEG electrodes for hairy sites. Wet electrodes require conductive gels, which will dry over the acquisition time, making them unstable for long-term EEG monitoring. Additionally, the electrode–scalp impedances of most dry electrodes are not adequate for high quality EEG collection at hairy sites. In view of the above problems, a flexible multi-layer semi-dry electrode was proposed for EEG monitoring in this study. The semi-dry electrode contains a flexible electrode body layer, foam layer and reservoir layer. The probe structure of the electrode body layer enables the electrode to work effectively at hairy sites. During long-term EEG monitoring, electrolytes stored in the reservoir layer are continuously released through the foam layer to the electrode–scalp interface, ensuring a lower electrode–scalp contact impedance. The experimental results showed that the average electrode–scalp impedance of the semi-dry electrode at a hairy site was only 23.89 ± 7.44 KΩ at 10 Hz, and it was lower than 40 KΩ over a long-term use of 5 h. The electrode performed well in both static and dynamic EEG monitoring, where the temporal correlation with wet electrode signals at the hairy site could reach 94.25% and 90.65%, respectively, and specific evoked EEG signals could be collected. The flexible multi-layer semi-dry electrode can be well applied to scalp EEG monitoring at hairy sites, providing a promising solution for daily long-term monitoring of wearable EEGs.

General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. ABSTRACTNovel CuO nanoparticle-capped ZnO nanorods have been produced using a pulsed laser deposition (PLD) method. These nanorods are shown to grow by a CuO-nanoparticle-assisted vapour-solid-solid (V-S-S) mechanism. The photoluminescence (PL) accompanying ultraviolet illumination of these capped nanorod samples shows large variations upon exposure to trace quantities of H 2 S gas. The present data suggests that both the Cu-doped ZnO stem and the CuO capping nanoparticle contribute to optical H 2 S sensing with these CuO-ZnO nanorods. This study represents the first demonstration of PL-based H 2 S gas sensing, at room temperature, with sub-ppm sensitivity. It also opens the way to producing CuO-ZnO nanorods by a V-S-S mechanism using gas phase methods other than PLD.2

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Ultrathin two-dimensional ZnO nanosheets (NSs) with thicknesses of just a few nanometers have been fabricated by a solvothermal method. The very large surface area to volume ratio of this material translates into outstanding electrical sensing responses to ethanol (as high as S 97 to 200 ppm of ethanol at a working temperature of 320 o C). Decorating these ZnO NSs with CuO nanoparticles (NPs), by pulsed laser ablation of a CuO target at room temperature and then post-annealing at 400 o C, yields CuO-ZnO NSs that display a further up to 2-fold enhanced response to ethanol vapour, reduced sensor response and recovery times, high sensing repeatability and high selectivity. Mechanism s underpinning the enhanced sensing properties of the CuO-ZnO NSs are discussed in terms of CuO NPinduced p-n junction depletion regions and increases in the density of active sites for ethanol adsorption and for reaction with adsorbed oxygen species.

Inhibition of bacterial nitric oxide synthase (bNOS) has the potential to improve the efficacy of antimicrobials used to treat infections by Gram-positive pathogens Staphylococcus aureus and Bacillus anthracis. However, inhibitor specificity toward bNOS over the mammalian NOS (mNOS) isoforms remains a challenge because of the near identical NOS active sites. One key structural difference between the NOS isoforms is the amino acid composition of the pterin cofactor binding site that is adjacent to the NOS active site. Previously, we demonstrated that a NOS inhibitor targeting both the active and pterin sites was potent and functioned as an antimicrobial (HoldenHolden24145412Proc. Natl. Acad. Sci. U.S.A.201311018127). Here we present additional crystal structures, binding analyses, and bacterial killing studies of inhibitors that target both the active and pterin sites of a bNOS and function as antimicrobials. Together, these data provide a framework for continued development of bNOS inhibitors, as each molecule represents an excellent chemical scaffold for the design of isoform selective bNOS inhibitors.