Celastrol inhibits aminoglycoside-induced ototoxicity via heat shock protein 32

Hearing loss is often caused by death of the mechanosensory hair cells of the inner ear. Hair cells are susceptible to death caused by aging, noise trauma, and ototoxic drugs, including the aminoglycoside antibiotics and the antineoplastic agent cisplatin. Ototoxic drugs result in permanent hearing loss for over 500 000 Americans annually. We showed previously that induction of heat shock proteins (HSPs) inhibits both aminoglycoside- and cisplatin-induced hair cell death in whole-organ cultures of utricles from adult mice. In order to begin to translate these findings into a clinical therapy aimed at inhibiting ototoxic drug-induced hearing loss, we have now examined a pharmacological HSP inducer, celastrol. Celastrol induced upregulation of HSPs in utricles, and it provided significant protection against aminoglycoside-induced hair cell death in vitro and in vivo. Moreover, celastrol inhibited hearing loss in mice receiving systemic aminoglycoside treatment. Our data indicate that the major heat shock transcription factor HSF-1 is not required for celastrol-mediated protection. HSP32 (also called heme oxygenase-1, HO-1) is the primary mediator of the protective effect of celastrol. HSP32/HO-1 inhibits pro-apoptotic c-Jun N-terminal kinase (JNK) activation and hair cell death. Taken together, our data indicate that celastrol inhibits aminoglycoside ototoxicity via HSP32/HO-1 induction

Aqueous-Phase Synthesis of Silver Nanodiscs and Nanorods in Methyl Cellulose Matrix: Photophysical Study and Simulation of UV–Vis Extinction Spectra Using DDA Method

We present a very simple and effective way for the synthesis of tunable coloured silver sols having different morphologies. The procedure is based on the seed-mediated growth approach where methyl cellulose (MC) has been used as soft-template in the growth solution. Nanostructures of varying morphologies as well as colour of the silver sols are controlled by altering the concentration of citrate in the growth solution. Similar to the polymers in the solution, citrate ions also dynamically adsorbed on the growing silver nanoparticles and promote one (1-D) and two-dimensional (2-D) growth of nanoparticles. Silver nanostructures are characterized using UV–vis and HR-TEM spectroscopic study. Simulation of the UV–vis extinction spectra of our synthesized silver nanostructures has been carried out using discrete dipole approximation (DDA) method

Setting benchmarks for modelling gas–surface interactions using coherent control of rotational orientation states

A fundamental and predictive understanding of molecule-surface interactions is challenging to obtain. Here the authors report an experimental technique allowing direct measurement of the scattering matrix, which reports on the coherent evolution of quantum states of a molecule scattering from a surface

Refining value-at-risk estimates using a Bayesian Markov-switching GJR-GARCH copula-EVT model

In this paper, we propose a model for forecasting Value-at-Risk (VaR) using a Bayesian Markov-switching GJR-GARCH(1,1) model with skewed Student’s-t innovation, copula functions and extreme value theory. A Bayesian Markov-switching GJR-GARCH(1,1) model that identifies non-constant volatility over time and allows the GARCH parameters to vary over time following a Markov process, is combined with copula functions and EVT to formulate the Bayesian Markov-switching GJR-GARCH(1,1) copula-EVT VaR model, which is then used to forecast the level of risk on financial asset returns. We further propose a new method for threshold selection in EVT analysis, which we term the hybrid method. Empirical and back-testing results show that the proposed VaR models capture VaR reasonably well in periods of calm and in periods of crisis

Non-invasive diagnosis of pulmonary hypertension from lung Doppler signal: a proof of concept study

Transthoracic Parametric Doppler (TPD) is a novel ultrasound technique recently developed for the investigation of pulmonary blood vessels. Lung Doppler Signals (LDS) recorded from TPD provide information regarding the functional mechanical characteristics of pulmonary blood vessels. We aimed to define the specific profile of LDS generated from TPD imaging in patients with pulmonary hypertension (PH), and to evaluate the diagnostic performance of LDS to detect PH using right heart catheterization (RHC) as gold standard reference. Seventy nine PH patients and 79 healthy controls matched for age, gender and BMI were recruited in a prospective case-control multicenter study. LDS recordings were performed by TPD consisting of a pulsed Doppler with a 2 MHz single element transducer. LDS were recorded within 24 h of RHC. Following LDS extraction, classification and performance evaluation were performed offline using a support vector machine (k-fold cross validation method). The best LDS parameters for PH detection were (1) peak velocity of the systolic (S) and diastolic (D) signals, (2) the rise slope of the S and D signals, and (3) time to peak of the S signal. Overall, the sensitivity and specificity of TPD for detection of PH were 82.7 % (95 % CI 81.3-84.1) and 87.4 % (95 % CI 86.3-88.5), respectively, with an area under the receiver operating curve of 0.95 (95 % CI 0.94-0.96). Detection rate of PH increased progressively with the level of mean pulmonary artery pressure. LDS recorded by TPD display a specific profile in PH and appears to be a promising and reliable tool for PH diagnosis. Further studies are required to confirm the clinical usefulness of LDS