Detection and characterization of nitric oxide synthase in the mammalian cochlea

The messenger molecule nitric oxide (NO) is involved in blood flow regulation, cytotoxicity, and neural signalling, processes that are important in the physiology and pathophysiology of the mammalian cochlea. However, neither the presence of NO nor its synthetic enzyme, NO synthase, has been established in the peripheral auditory system. NO synthase activity, measured as the enzymatic conversion of radioactive arginine to citrulline, was predominantly soluble in the auditory nerve, lateral wall, vetibule and cochlear neuroepithelium. and trifluoperazine inhibited NO synthase activity in the lateral wall and auditory nerve. Histochemical staining by NADPH-diaphorase localized NOS activity to the lateral wall and the neuronal elements of the organ of Corti. Based on these results, the predominant NO synthase isoform in the cochlea is the neuronal type-I isoform.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31105/1/0000001.pd

Indirect X-ray detectors based on inkjet-printed photodetectors with a screen-printed scintillator layer

Organic photodetectors (PDs) based on printing technologies will allow to expand the current field of PD applications toward large-area and flexible applications in areas such as medical imaging, security, and quality control, among others. Inkjet printing is a powerful digital tool for the deposition of smart and functional materials on various substrates, allowing the development of electronic devices such as PDs on various substrates. In this work, inkjet-printed PD arrays, based on the organic thin-film transistor architecture, have been developed and applied for the indirect detection of X-ray radiation using a scintillator ink as an X-ray absorber. The >90% increase of the photocurrent of the PDs under X-ray radiation, from about 53 nA without the scintillator film to about 102 nA with the scintillator located on top of the PD, proves the suitability of the developed printed device for X-ray detection applicationsThe authors thank FEDER funds through the COMPETE 2020 Programme and National Funds through FCT-Portuguese Foundation for Science and Technology under Strategic Funding UID/FIS/04650/2013 and projects PTDC/EEI-SII/5582/2014, PTDC/CTM-ENE/5387/2014 and in the framework of EuroNanoMed 2016 call, Project LungChek ENMed/0049/2016. J.O. and V.C. thank the FCT for the SFRH/BD/98219/2013 and SFRH/BPD/97739/2013 grants, respectively. The authors acknowledge funding by the Spanish Ministry of Economy and Competitiveness (MINECO) through the project MAT2016-76039-C4-3-R. Financial support from the Basque Government Industry Department under the ELKARTEK program is also acknowledged. The authors thank Iain McCulloch and Martin Heeney from Flexink for providing the OSC. Dirk Rittrich (Department Layer Deposition at Fraunhofer ENAS) is acknowledged for the FIB/SEM analysis and the sample preparation. R.D.R acknowledges the DFG Unit FOR1317 SMINT, the Cluster of Excellence, and the Tomsk Polytechnic University Competitiveness Enhancement Program grant TPU CEP_IHTP_73\2017. This work was performed in the context of the European COST Action MP1302 Nanospectroscopy.info:eu-repo/semantics/publishedVersio

An Src-protein tyrosine kinase inhibitor to reduce cisplatin ototoxicity while preserving its antitumor effect

Ototoxicity remains a major dose-limiting side effect of cisplatin. The current studies were carried out to evaluate the effectiveness of a novel Src-protein tyrosine kinase inhibitor in protecting the ear from cisplatin ototoxicity without compromising cisplatin's antitumor effects. The Src inhibitor has been shown to be effective in protecting the ear from noise-induced hearing loss. Three studies were carried out to determine whether this compound has otoprotective activity in rats treated with cisplatin. The first two studies used the Src inhibitor as a cotreatment with single doses of cisplatin in Fischer 344/NHsd rats and nude rats, respectively. Cochlear damage was assessed by auditory brainstem response threshold shifts and outer hair cell loss. The third study was carried out in nude rats with implanted HT-29 tumors, and the Src inhibitor was administered as a cotreatment with a lower dose of cisplatin. Cochlear damage and changes in tumor volume were assessed in the third study. In the first two studies, cotreatment with the Src inhibitor reduced cisplatin-induced hearing loss significantly. In the third study, little hearing loss was induced because of the use of a lower dose of cisplatin. However, cotreatment with the Src inhibitor did not exert a negative effect on cisplatin's slowing of tumor growth in the treated rats. The findings suggest that the Src inhibitor may provide an effective cotreatment with cisplatin to reduce cisplatin's ototoxicity, without compromising its antitumor capability

Two distinct Ca2+ dependent signaling pathways regulate the motor output of cochlear outer hair cells

The outer hair cells (OHCs) of the cochlea have an electromotility mechanism, based on conformational changes of voltage-sensitive "motor" proteins in the lateral plasma membrane. The translocation of electrical charges across the membrane that accompanies electromotility imparts a voltage dependency to the membrane capacitance. We used capacitance measurements to investigate whether electromotility may be influenced by different manipulations known to affect intracellular Ca2+ or Ca2+-dependent protein phosphorylation. Application of acetylcholine (ACh) to the synaptic pole of isolated OHCs evoked a Ca2+-activated apamin-sensitive outward K+ current. It also enhanced electromotility, probably because of a phosphorylation-dependent decrease of the cell's axial stiffness. However, ACh did not change the voltage-dependent capacitance either in conventional whole-cell experiments or under perforated-patch conditions. The effects produced by the Ca2+ ionophore ionomycin mimicked those produced by ACh. Hyperpolarizing shifts of the voltage dependence of capacitance and electromotility were induced by okadaic acid, a promoter of protein phosphorylation, whereas trifluoperazine and W-7, antagonists of calmodulin, caused opposite depolarizing shifts. Components of the protein phosphorylation cascade-IP3 receptors and calmodulin-dependent protein kinase type IV-were immunolocalized to the lateral wall of the OHC. Our results suggest that two different Ca2+-dependent pathways may control the OHC motor output. The first pathway modulates cytoskeletal stiffness and can be activated by ACh. The second pathway shifts the voltage sensitivity of the OHC electromotile mechanism and may be activated by the release of Ca2+ from intracellular stores located in the proximity of the lateral plasma membrane

An Src-protein tyrosine kinase inhibitor to reduce cisplatin ototoxicity while preserving its antitumor effect

Ototoxicity remains a major dose-limiting side effect of cisplatin. The current studies were carried out to evaluate the effectiveness of a novel Src-protein tyrosine kinase inhibitor in protecting the ear from cisplatin ototoxicity without compromising cisplatin's antitumor effects. The Src inhibitor has been shown to be effective in protecting the ear from noise-induced hearing loss. Three studies were carried out to determine whether this compound has otoprotective activity in rats treated with cisplatin. The first two studies used the Src inhibitor as a cotreatment with single doses of cisplatin in Fischer 344/NHsd rats and nude rats, respectively. Cochlear damage was assessed by auditory brainstem response threshold shifts and outer hair cell loss. The third study was carried out in nude rats with implanted HT-29 tumors, and the Src inhibitor was administered as a cotreatment with a lower dose of cisplatin. Cochlear damage and changes in tumor volume were assessed in the third study. In the first two studies, cotreatment with the Src inhibitor reduced cisplatin-induced hearing loss significantly. In the third study, little hearing loss was induced because of the use of a lower dose of cisplatin. However, cotreatment with the Src inhibitor did not exert a negative effect on cisplatin's slowing of tumor growth in the treated rats. The findings suggest that the Src inhibitor may provide an effective cotreatment with cisplatin to reduce cisplatin's ototoxicity, without compromising its antitumor capability