Cyp1 Inhibition Prevents Doxorubicin-Induced Cardiomyopathy in a Zebrafish Heart-Failure Model

Doxorubicin is a highly effective chemotherapy agent used to treat many common malignancies. However, its use is limited by cardiotoxicity, and cumulative doses exponentially increase the risk of heart failure. To identify novel heart failure treatment targets, a zebrafish model of doxorubicin-induced cardiomyopathy was previously established for small-molecule screening. Using this model, several small molecules that prevent doxorubicin-induced cardiotoxicity both in zebrafish and in mouse models have previously been identified. In this study, exploration of doxorubicin cardiotoxicity is expanded by screening 2271 small molecules from a proprietary, target-annotated tool compound collection. It is found that 120 small molecules can prevent doxorubicin-induced cardiotoxicity, including 7 highly effective compounds. Of these, all seven exhibited inhibitory activity towards cytochrome P450 family 1 (CYP1). These results are consistent with previous findings, in which visnagin, a CYP1 inhibitor, also prevents doxorubicin-induced cardiotoxicity. Importantly, genetic mutation of cyp1a protected zebrafish against doxorubicin-induced cardiotoxicity phenotypes. Together, these results provide strong evidence that CYP1 is an important contributor to doxorubicin-induced cardiotoxicity and highlight the CYP1 pathway as a candidate therapeutic target for clinical cardioprotection.     

Performance Evaluation of Inversion Mode and Junctionless Dual-Material Double-Surrounding Gate Si Nanotube MOSFET for 5-nm Gate Length

Semiconductors - In this work, drain current ID for 5-nm gate length with dual-material (DM) double-surrounding gate (DSG) inversion mode (IM) and junctionless (JL) silicon nanotube (SiNT) MOSFET...     

Nanostructured poly(3-hexylthiophene-2,5-diyl) films with tunable dimensions through self-assembly with polystyrene

Poly(3-hexylthiophene-2,5-diyl) is among the most widely used conjugated polymers for opto-electronic applications. To enhance its properties, researchers have attempted to nanostructure this polymer using various processes including breath figure arrays, nanolithography and elaborated organic synthesis. We here demonstrate a simple process to nanostructure the conjugated polymer using self-assembly with polystyrene and selective removal of one of the phases. The influence of the molecular weight of each polymer on the thin film morphology was systematically studied by atomic force microscopy. Using this approach, we observe two types of nanostructure, namely, nanoporous and nanoisland structures, of which the dimensions can be tuned by modifying the molecular weight of each polymer in the blend. This simple process introduces a cost-effective alternative to produce thin films of conjugated polymer with average nano-features from 100 nm up to 500 nm which could be used in a wide range of applications.     

Studies on oxidation of benzo [a] pyrene by sunlight and ozone

The destruction of the carcinogen benzo[a]pyrene (BaP) by light is well known; laboratory workers are routinely advised to cover fluorescent lamps with yellow filters while treating samples containing BaP. However until recently the mechanism of oxidation by sunlight and ozone had not been studied in detail. Concentrations of benzo[a]pyrene in urban air are in the range of 5–10 μg/1000 m³. Oxidant concentrations (predominantly in the form of ozone) are reported to be in the range of 0.01 ppm (22 μg per m³). Thus a sampling system with a filter paper would filter about 22,000 μg of ozone passing through and collect about 5 μg of BaP for analysis. The effect of interactions of such large ozone concentrations with BaP deposited on the filter paper is reported; data for the oxidation rates for benzo[a]pyrene coated on quartz surface and exposed to ozone or sunlight are presented. The oxidation products were analysed by thin-layer chromatography and highpressure liquid chromatography. From about eight products detected in these experiments, three have been identified as quinones based on UV-absorption spectrometry and mass spectrometry. Oxidation rates as high as 100% per hour of exposure are observed when less than 0.1 μg of BaP is coated inside the quartz tubes and exposed to ozone or sunlight. Oxidation rates for benzo[a]pyrene (using tritiated BaP) were determined for two types of experimental conditions. In the first set, tritiated BaP was spotted onto a glass fibre paper and sampling continued for 24 h; the loss of BaP was found to be 88%. In the second set tritiated BaP was spotted at intervals of one hour, for eight hours, while sampling is being carried out and the loss of BaP during the period was estimated to be 50%.     

Similarity between class A and class B G-protein-coupled receptors exemplified through calcitonin gene-related peptide receptor modelling and mutagenesis studies

Modelling class B G-protein-coupled receptors (GPCRs) using class A GPCR structural templates is difficult due to lack of homology. The plant GPCR, GCR1, has homology to both class A and class B GPCRs. We have used this to generate a class A–class B alignment, and by incorporating maximum lagged correlation of entropy and hydrophobicity into a consensus score, we have been able to align receptor transmembrane regions. We have applied this analysis to generate active and inactive homology models of the class B calcitonin gene-related peptide (CGRP) receptor, and have supported it with site-directed mutagenesis data using 122 CGRP receptor residues and 144 published mutagenesis results on other class B GPCRs. The variation of sequence variability with structure, the analysis of polarity violations, the alignment of group-conserved residues and the mutagenesis results at 27 key positions were particularly informative in distinguishing between the proposed and plausible alternative alignments. Furthermore, we have been able to associate the key molecular features of the class B GPCR signalling machinery with their class A counterparts for the first time. These include the [K/R]KLH motif in intracellular loop 1, [I/L]xxxL and KxxK at the intracellular end of TM5 and TM6, the NPXXY/VAVLY motif on TM7 and small group-conserved residues in TM1, TM2, TM3 and TM7. The equivalent of the class A DRY motif is proposed to involve Arg^2.39, His^2.43 and Glu^3.46, which makes a polar lock with T^6.37. These alignments and models provide useful tools for understanding class B GPCR function.     

Preparation and characterization of thin films of electrodeposited CdTe semiconductors

Thin films of CdTe semiconductors were prepared by electrodeposition technique in aqueous solutions. The deposition mechanism was investigated by cyclic voltammetry. The potential regions for the formation of the n-CdTe and p-CdTe films were determined. The structure, composition and morphology characteristics of as-deposited thin films of CdTe grown on SnO₂/glass and CdS/SnO₂/glass were investigated by XRD, EDAX and SEM techniques. The optical properties were measured to determine the absorption coefficient and band gap values. The as-deposited CdTe films grown on SnO₂/glass contained free Te while those grown on CdS/SnO₂/Glass did not contain this phase. The CdTe has the cubic structure with strong (111) orientation. The EDAX analysis showed a nearly stiochiometric Cd:Te ratio. The band gap has a value of 1.48 eV, which is in a good accordance with those reported in the literature. The effect of annealing at 350 and 400°C after CdCl₂ treatment on the structure and morphology was also examined.     

Pulse control of flexible multibody systems

An active pulse control method is developed to reduce the vibrations of multibody systems resulting from impact loadings. The pulse, which is a function of system generalized coordinates and velocities, is determined analytically using energy and momentum balance equations of the impacting bodies. Elastic components in the multibody system are discretized using the finite element method. The system equations of motions and nonlinear algebraic constraint equations describing mechanical joints between different components are written in the Lagrangian formulation using a finite set of coupled reference position and local elastic generalized coordinates. A set of independent differential equations are identified by the generalized coordinate partitioning of the constraint Jacobian matrix. These equations are written in the state space formulation and integrated forward in time using a direct numerical integration method. Dependent coordinates are then determined using the constraint kinematic relations. Points in time at which impact occurs are monitored by an impact predictor function, which controls the integration algorithms and forces for the solution of the momentum relation, to define the jump discontinuities in the composite velocity vector as well as the system reaction forces. The effectiveness of the active pulse control in reducing the vibration of flexible multibody aircraft during the touchdown impact is investigated and numerical results are presented.     

High speed continuous and interrupted dry turning of A390 Aluminum/Silicon Alloy using nanostructured diamond coated WC–6 wt.% cobalt tool inserts by MPCVD

Nanostructured diamond films were grown to a thickness of approximately 35 µm by a 30 kW, 915 MHz, microwave plasma-assisted chemical vapor deposition (MPCVD) on chemically treated WC–6 wt.% Co tool inserts. Rockwell indentation tests were performed to evaluate the adhesion of the films and compared to that of traditional microcrystalline diamond. A series of high speed dry turning tests on high-silicon (18 wt.% Si) aluminum alloy A390 under continuous and interrupted modes were performed and comparisons were carried out to investigate the wear behavior on tool inserts that were uncoated, coated with nanostructured diamond, and commercial PCD (polycrystalline diamond cutter) ones. The tests showed that nanostructured diamond coatings demonstrated excellent durability against the highly abrasive A390 aluminum–silicon alloys in high speed dry turning. Ultra fine grain structure of this coating produces workpiece surface finish comparable or even better than PCD tools in the range we studied. Excellent coating adhesion of nanostructured diamond on WC–6% Co substrates leads to reliable wear behavior. For the first time, we evaluated the performance of nanostructured diamond film coated insert under high speed interrupted turning mode. A “self-cleaning” mechanism was observed which can significantly improve the performance of nanostructured diamond films. Micro-Raman spectra were taken on tested tools to study the wear mechanism of the coating.     

Reflective digital optical switch (RDOS) for DWDM optical networkapplications

A novel, high-performance, reflective digital optical switch for use in dense wavelength-division-multiplexed (WDM) network applications is presented. Highly reliable Ti-LiNbO₃ devices show high-speed polarization-independent reflection modulation with 30-dB ON-OFF ratios over a wavelength range from 1520 to 1570 nm