Small molecule dual-inhibitors of TRPV4 and TRPA1 for attenuation of inflammation and pain.

TRPV4 ion channels represent osmo-mechano-TRP channels with pleiotropic function and wide-spread expression. One of the critical functions of TRPV4 in this spectrum is its involvement in pain and inflammation. However, few small-molecule inhibitors of TRPV4 are available. Here we developed TRPV4-inhibitory molecules based on modifications of a known TRPV4-selective tool-compound, GSK205. We not only increased TRPV4-inhibitory potency, but surprisingly also generated two compounds that potently co-inhibit TRPA1, known to function as chemical sensor of noxious and irritant signaling. We demonstrate TRPV4 inhibition by these compounds in primary cells with known TRPV4 expression - articular chondrocytes and astrocytes. Importantly, our novel compounds attenuate pain behavior in a trigeminal irritant pain model that is known to rely on TRPV4 and TRPA1. Furthermore, our novel dual-channel blocker inhibited inflammation and pain-associated behavior in a model of acute pancreatitis - known to also rely on TRPV4 and TRPA1. Our results illustrate proof of a novel concept inherent in our prototype compounds of a drug that targets two functionally-related TRP channels, and thus can be used to combat isoforms of pain and inflammation in-vivo that involve more than one TRP channel. This approach could provide a novel paradigm for treating other relevant health conditions.

Dosimetric Evaluation of Metal Artefact Reduction using Metal Artefact Reduction (MAR) Algorithm and Dual-energy Computed Tomography (CT) Method

Purpose: Computed Tomography (CT) is one of the standard diagnostic imaging modalities for the evaluation of a patient’s medical condition. In comparison to other imaging modalities such as Magnetic Resonance Imaging (MRI), CT is a fast acquisition imaging device with higher spatial resolution and higher contrast-to-noise ratio (CNR) for bony structures. CT images are presented through a gray scale of independent values in Hounsfield units (HU). High HU-valued materials represent higher density. High density materials, such as metal, tend to erroneously increase the HU values around it due to reconstruction software limitations. This problem of increased HU values due to metal presence is referred to as metal artefacts. Hip prostheses, dental fillings, aneurysm clips, and spinal clips are a few examples of metal objects that are of clinical relevance. These implants create artefacts such as beam hardening and photon starvation that distort CT images and degrade image quality. This is of great significance because the distortions may cause improper evaluation of images and inaccurate dose calculation in the treatment planning system. Different algorithms are being developed to reduce these artefacts for better image quality for both diagnostic and therapeutic purposes. However, very limited information is available about the effect of artefact correction on dose calculation accuracy. This research study evaluates the dosimetric effect of metal artefact reduction algorithms on severe artefacts on CT images. This study uses Gemstone Spectral Imaging (GSI)-based MAR algorithm, projection-based Metal Artefact Reduction (MAR) algorithm, and the Dual-Energy method.

Materials and Methods: The Gemstone Spectral Imaging (GSI)-based and SMART Metal Artefact Reduction (MAR) algorithms are metal artefact reduction protocols embedded in two different CT scanner models by General Electric (GE), and the Dual-Energy Imaging Method was developed at Duke University. All three approaches were applied in this research for dosimetric evaluation on CT images with severe metal artefacts. The first part of the research used a water phantom with four iodine syringes. Two sets of plans, multi-arc plans and single-arc plans, using the Volumetric Modulated Arc therapy (VMAT) technique were designed to avoid or minimize influences from high-density objects. The second part of the research used projection-based MAR Algorithm and the Dual-Energy Method. Calculated Doses (Mean, Minimum, and Maximum Doses) to the planning treatment volume (PTV) were compared and homogeneity index (HI) calculated.

Results: (1) Without the GSI-based MAR application, a percent error between mean dose and the absolute dose ranging from 3.4-5.7% per fraction was observed. In contrast, the error was decreased to a range of 0.09-2.3% per fraction with the GSI-based MAR algorithm. There was a percent difference ranging from 1.7-4.2% per fraction between with and without using the GSI-based MAR algorithm. (2) A range of 0.1-3.2% difference was observed for the maximum dose values, 1.5-10.4% for minimum dose difference, and 1.4-1.7% difference on the mean doses. Homogeneity indexes (HI) ranging from 0.068-0.065 for dual-energy method and 0.063-0.141 with projection-based MAR algorithm were also calculated.

Conclusion: (1) Percent error without using the GSI-based MAR algorithm may deviate as high as 5.7%. This error invalidates the goal of Radiation Therapy to provide a more precise treatment. Thus, GSI-based MAR algorithm was desirable due to its better dose calculation accuracy. (2) Based on direct numerical observation, there was no apparent deviation between the mean doses of different techniques but deviation was evident on the maximum and minimum doses. The HI for the dual-energy method almost achieved the desirable null values. In conclusion, the Dual-Energy method gave better dose calculation accuracy to the planning treatment volume (PTV) for images with metal artefacts than with or without GE MAR Algorithm.

Effective Dose Estimation in Fast-kV Switch Dual Energy Computed Tomography

Purpose

The objective of our study was to test a new approach to approximating organ dose by using the effective energy of the combined 80kV/140kV beam used in fast kV switch dual-energy (DE) computed tomography (CT). The two primary focuses of the study were to first validate experimentally the dose equivalency between MOSFET and ion chamber (as a gold standard) in a fast kV switch DE environment, and secondly to estimate effective dose (ED) of DECT scans using MOSFET detectors and an anthropomorphic phantom.

Materials and Methods

A GE Discovery 750 CT scanner was employed using a fast-kV switch abdomen/pelvis protocol alternating between 80 kV and 140 kV. The specific aims of our study were to (1) Characterize the effective energy of the dual energy environment; (2) Estimate the f-factor for soft tissue; (3) Calibrate the MOSFET detectors using a beam with effective energy equal to the combined DE environment; (4) Validate our calibration by using MOSFET detectors and ion chamber to measure dose at the center of a CTDI body phantom; (5) Measure ED for an abdomen/pelvis scan using an anthropomorphic phantom and applying ICRP 103 tissue weighting factors; and (6) Estimate ED using AAPM Dose Length Product (DLP) method. The effective energy of the combined beam was calculated by measuring dose with an ion chamber under varying thicknesses of aluminum to determine half-value layer (HVL).

Results

The effective energy of the combined dual-energy beams was found to be 42.8 kV. After calibration, tissue dose in the center of the CTDI body phantom was measured at 1.71 ± 0.01 cGy using an ion chamber, and 1.73±0.04 and 1.69±0.09 using two separate MOSFET detectors. This result showed a -0.93% and 1.40 % difference, respectively, between ion chamber and MOSFET. ED from the dual-energy scan was calculated as 16.49 ± 0.04 mSv by the MOSFET method and 14.62 mSv by the DLP method.

Individual Proton Pump Inhibitors and Outcomes in Patients With Coronary Artery Disease on Dual Antiplatelet Therapy: A Systematic Review.

BACKGROUND: Observational studies evaluating the possible interaction between proton pump inhibitors (PPIs) and clopidogrel have shown mixed results. We conducted a systematic review comparing the safety of individual PPIs in patients with coronary artery disease taking clopidogrel. METHODS AND RESULTS: Studies performed from January 1995 to December 2013 were screened for inclusion. Data were extracted, and study quality was graded for 34 potential studies. For those studies in which follow-up period, outcomes, and multivariable adjustment were comparable, meta-analysis was performed.The adjusted odds or hazard ratios for the composite of cardiovascular or all-cause death, myocardial infarction, and stroke at 1 year were reported in 6 observational studies with data on individual PPIs. Random-effects meta-analyses of the 6 studies revealed an increased risk for adverse cardiovascular events for those taking pantoprazole (hazard ratio 1.38; 95% CI 1.12-1.70), lansoprazole (hazard ratio 1.29; 95% CI 1.09-1.52), or esomeprazole (hazard ratio 1.27; 95% CI 1.02-1.58) compared with patients on no PPI. This association was not significant for omeprazole (hazard ratio 1.16; 95% CI 0.93-1.44). Sensitivity analyses for the coronary artery disease population (acute coronary syndrome versus mixed) and exclusion of a single study due to heterogeneity of reported results did not have significant influence on the effect estimates for any PPIs. CONCLUSIONS: Several frequently used PPIs previously thought to be safe for concomitant use with clopidogrel were associated with greater risk of adverse cardiovascular events. Although the data are observational, they highlight the need for randomized controlled trials to evaluate the safety of concomitant PPI and clopidogrel use in patients with coronary artery disease.

Dual-band Filtenna Array for WLAN Applications

This paper presents the design and results of a dual-band antenna array integrated with bandpass filters for WLAN applications. The array is fed with a single 50 Ω port and consists of two radiating elements; thereby having a 1x2 array structure. The two bands of the antenna array correspond to the two WLAN bands of 2.4 GHz and 5.8 GHz. A standalone array has first been designed. Other than the two fundamental resonant frequencies, the standalone array exhibits spurious harmonics at various other frequencies. For the suppression of these harmonics, the array has been integrated with two bandpass filters, centered at 2.4 GHz and 5.8 GHz. The resulting filtenna array was simulated, fabricated and measured. Obtained simulation and measurement results agree well with each other and have been presented to validate the accuracy of the proposed structure. Measured return loss of the structure shows dual-bands at 2.4 GHz and 5.8 GHz of more than 30 dB each and also a successful suppression of the spurious harmonics of the antenna array has been achieved. Radiation patterns have also been simulated and measured and both results shown. The gain and efficiency have also been presented; with the values being 6.7 dBi and 70% for the 2.4 GHz band and 7.4 dBi and 81% for the 5.8 GHz band respectively.

Joint Compensation of I/Q Impairments and PA Nonlinearity for Concurrent Dual-Band Transmitters using Two-Box Model

A novel two-box model for joint compensation of nonlinear distortion introduced from both in-phase/quadrature modulator and power amplifier is proposed for concurrent dual-band wireless transmitters. Compensation of nonlinear distortion is accomplished in two phases, where phases are identified separately. It is shown that complexity of the digital predistortion is reduced. The performance of the proposed model is evaluated in terms of ACPR, EVM and NMSE improvements using 1.4 MHz LTE and WCDMA signals.

Digital geometric-sequence control technique for bidirectional dual active bridge DC-DC converters used in future electric vehicles

Bidirectional DC-DC converters are widely used in different applications such as energy storage systems, Electric Vehicles (EVs), UPS, etc. In particular, future EVs require bidirectional power flow in order to integrate energy storage units into smart grids. These bidirectional power converters provide Grid to Vehicle (V2G)/ Vehicle to Grid (G2V) power flow capability for future EVs. Generally, there are two control loops used for bidirectional DC-DC converters: The inner current loop and The outer loop. The control of DAB converters used in EVs are proved to be challenging due to the wide range of operating conditions and non-linear behavior of the converter. In this thesis, the precise mathematical model of the converter is derived and non-linear control schemes are proposed for the control system of bidirectional DC-DC converters based on the derived model. The proposed inner current control technique is developed based on a novel Geometric-Sequence Control (GSC) approach. The proposed control technique offers significantly improved performance as compared to one for conventional control approaches. The proposed technique utilizes a simple control algorithm which saves on the computational resources. Therefore, it has higher reliability, which is essential in this application. Although, the proposed control technique is based on the mathematical model of the converter, its robustness against parameter uncertainties is proven. Three different control modes for charging the traction batteries in EVs are investigated in this thesis: the voltage mode control, the current mode control, and the power mode control. The outer loop control is determined by each of the three control modes. The structure of the outer control loop provides the current reference for the inner current loop. Comprehensive computer simulations have been conducted in order to evaluate the performance of the proposed control methods. In addition, the proposed control have been verified on a 3.3 kW experimental prototype. Simulation and experimental results show the superior performance of the proposed control techniques over the conventional ones.

Reconfigurable UWB Filtennas with Dual Bandnotch for Unwanted Bands using Graphene based Switches

Presented are the design and results of a reconfigurable UWB filtenna with sharp dual bandnotch at WiMAX 3.5 GHz and WLAN 5.8 GHz bands. The filtenna is formed by placing three loop resonators in an UWB antenna. The resonators are fitted with Graphene based switches which introduce reconfigurability. The filtenna was simulated electromagnetically and with Graphene based switches in switches OFF and switches ON states. Presented results show a passband from 2.81–12.27 GHz in OFF state and ON state results in sharp dual bandnotch within the passband at 3.45 and 5.95 GHz at a return loss of 2–2.5 dB. The gain and efficiency in both states has also been given and is reduced in ON state at the dual bandnotch. The radiation patterns in E- and H-planes are stable.

Highly linear reconfigurable UWB filters with independently controlled dual bandnotch

This letter proposes a high-linearity reconfigurable lower ultra-wideband (3.1–5.25 GHz) filter with independently controlled dual bandnotch at WiMAX 3.5 GHz band and satellite communication systems 4.2 GHz band. Reconfigurability has been achieved by the implementation of Graphene based switches (simulation only) and PIN diodes (measurements). The simulation and measurement results in OFF state show an entire bandpass response from 3.1 GHz to 5.25 GHz and with a very low insertion loss. In ON state, the results show that sharp rejections at 3.5 GHz and 4.2 GHz are achieved, with a low passband insertion loss. The two bandnotch operate independently of each other; thus allowing to control the behaviour of the required bandnotch. The third order intermodulation products were also measured in OFF and ON states and the linearity results have been presented. The filter is able to achieve a high performance with good linearity and no significant loss.

Survival or death: a dual role of autophagy in stress-induced pericyte loss in diabetic retinopathy

Aims/hypothesis
Intra-retinal extravasation and modification of LDL have been implicated in diabetic retinopathy: autophagy may mediate these effects.
Methods
Immunohistochemistry was used to detect autophagy marker LC3B in human and murine diabetic and non-diabetic retinas. Cultured human retinal capillary pericytes (HRCPs) were treated with in vitro-modified heavily-oxidised glycated LDL (HOG-LDL) vs native LDL (N-LDL) with or without autophagy modulators: green fluorescent protein–LC3 transfection; small interfering RNAs against Beclin-1, c-Jun NH(2)-terminal kinase (JNK) and C/EBP-homologous protein (CHOP); autophagy inhibitor 3-MA (5 mmol/l) and/or caspase inhibitor Z-VAD-fmk (100 μmol/l). Autophagy, cell viability, oxidative stress, endoplasmic reticulum stress, JNK activation, apoptosis and CHOP expression were assessed by western blots, CCK-8 assay and TUNEL assay. Finally, HOG-LDL vs N-LDL were injected intravitreally to STZ-induced diabetic vs control rats (yielding 50 and 200 mg protein/l intravitreal concentration) and, after 7 days, retinas were analysed for ER stress, autophagy and apoptosis.
Results
Intra-retinal autophagy (LC3B staining) was increased in diabetic vs non-diabetic humans and mice. In HRCPs, 50 mg/l HOG-LDL elicited autophagy without altering cell viability, and inhibition of autophagy decreased survival. At 100–200 mg/l, HOG-LDL caused significant cell death, and inhibition of either autophagy or apoptosis improved survival. Further, 25–200 mg/l HOG-LDL dose-dependently induced oxidative and ER stress. JNK activation was implicated in autophagy but not in apoptosis. In diabetic rat retina, 50 mg/l intravitreal HOG-LDL elicited autophagy and ER stress but not apoptosis; 200 mg/l elicited greater ER stress and apoptosis.
Conclusions
Autophagy has a dual role in diabetic retinopathy: under mild stress (50 mg/l HOG-LDL) it is protective; under more severe stress (200 mg/l HOG-LDL) it promotes cell death.

A bimetallic catalyst on a dual component support for low temperature total methane oxidation

Palladium, platinum bimetallic catalysts supported on η-Al₂O₃, ZSM-5(23) and ZSM-5(80), with and without the addition of TiO₂, were prepared and used for low temperature total methane oxidation (TMO). The catalysts were tested under reaction temperatures of 200-500 °C with a GHSV of 100,000 mL g^-1 h^-1. It was found that all four components, palladium, platinum, an acidic support and oxygen carrier were needed to achieve a highly active and stable catalyst. The optimum support being 17.5% TiO₂ on ZSM-5(80) where the T_10% was observed at only 200 °C. On addition of platinum, longer time on stream experiments showed no decrease in the catalyst activity over 50 h at 250 °C.

Dual roles of DNA repair enzymes in RNA biology/post-transcriptional control

Despite consistent research into the molecular principles of the DNA damage repair pathway for almost two decades, it has only recently been found that RNA metabolism is very tightly related to this pathway, and the two ancient biochemical mechanisms act in alliance to maintain cellular genomic integrity. The close links between these pathways are well exemplified by examining the base excision repair pathway, which is now well known for dual roles of many of its members in DNA repair and RNA surveillance, including APE1, SMUG1, and PARP1. With additional links between these pathways steadily emerging, this review aims to provide a summary of the emerging roles for DNA repair proteins in the post-transcriptional regulation of RNAs. 

Broadband Dual-Polarized Antenna with High Port Isolation and Polarization Purity

This paper presents a novel high symmetry balun which significantly improves the performance of dipole-based dual-polarized antennas. The new balun structure provides enhanced differential capability leading to high performance in terms of port-to-port isolation and far-field cross polarization. An example antenna using this balun is proposed. The simulated results show 53.5% of fractional bandwidth within the band 1.71−2.96 GHz (VSWR<1.5) and port-to-port isolation >59 dB. The radiation characteristic shows around 9 dBi of gain and far-field cross polarization <−48 dBi over the entire bandwidth. The detailed balun functioning and full antenna measurements will be presented during the conference. Performance comparison with similar structures will be also provided.