Upregulation of Haploinsufficient Gene Expression in the Brain by Targeting a Long Non-coding RNA Improves Seizure Phenotype in a Model of Dravet Syndrome

AbstractDravet syndrome is a devastating genetic brain disorder caused by heterozygous loss-of-function mutation in the voltage-gated sodium channel gene SCN1A. There are currently no treatments, but the upregulation of SCN1A healthy allele represents an appealing therapeutic strategy. In this study we identified a novel, evolutionary conserved mechanism controlling the expression of SCN1A that is mediated by an antisense non-coding RNA (SCN1ANAT). Using oligonucleotide-based compounds (AntagoNATs) targeting SCN1ANAT we were able to induce specific upregulation of SCN1A both in vitro and in vivo, in the brain of Dravet knock-in mouse model and a non-human primate. AntagoNAT-mediated upregulation of Scn1a in postnatal Dravet mice led to significant improvements in seizure phenotype and excitability of hippocampal interneurons. These results further elucidate the pathophysiology of Dravet syndrome and outline a possible new approach for the treatment of this and other genetic disorders with similar etiology

Preparation and mechanical properties of aluminum-doped zinc oxide transparent conducting films

Aluminum-doped zinc oxide transparent conducting films were deposited in this study by magnetron sputtering under different sputtering powers and substrate temperatures. At low sputtering powers and substrate temperatures, the deposited films were constructed by spherical grains. With increasing power and temperature, the grains became facet with an obvious (002) preferred orientation. The crystallinity and grain size of the films increased as well, and consequently the electrical resistivity decreased. By nanoindentation tests, the hardness of the deposited films was measured and found to increase from 8 to 10 GPa with higher sputtering power and substrate temperature because of higher densification and crystallinity. During nanoindentation and nanoscratch tests, interface delamination occurred between the films and substrates, and the interface adhesion energy was accordingly obtained. From the measurement of nanoscratch tests, the adhesion energy was found to be improved from 0.49 to 0.86 or 0.79 J/m(2), respectively, with higher sputtering power or substrate temperature because of the deeper penetration, higher densification and easier interface reaction of the deposited films. (C) 2008 Elsevier B.V. All rights reserved

The effect of post-fire-curing on strength velocity relationship for nondestructive assessment of fire-damaged concrete strength

This paper investigates the residual compressive strength and ultrasonic pulse velocity (UPV) of concrete, which has been water-cured after exposure to high temperatures. The relationship between the residual strength ratio and the residual UPV ratio was developed. Cylindrical specimens were made of concrete with water-cement ratios of 0.58 and 0.68 and, after 90 days, the specimens were heated in an electric furnace to temperatures ranging from 400 to 1000 degrees C. The concrete specimens exposed to elevated temperatures were cured in a water tank for 72 h and tested after 4, 27, 87 and 177 days. The ultrasonic pulse velocity and compressive strength of each post-fire-curing specimen were measured. Experimental results show that water curing of the concrete specimens after exposure to high temperatures has noticeable effects on the residual strength and UPV recovery. It is also shown that a change in the mixture proportion of concrete does not have a significant effect on the residual strength ratio and the residual UPV ratio of concrete subjected to elevated temperatures. The relationship between the residual strength ratio and the residual UPV ratio was developed and a general equation is proposed for predicting the residual strength of post-fire-curing concrete. Finally, this paper verifies the validity of the proposed equation for predicting the residual strength ratios of post-fire-curing concrete with the measured residual UPV ratios. (C) 2011 Elsevier Ltd. All rights reserved

Influences of reinforcing bars on crack depth measurement by stress waves

A research program was undertaken to evaluate the influences of steel reinforcing bars oil signals obtained from depth measurements of sui face-opening cracks in reinforced concrete structures based on transient stress waves generated by elastic impact. Numerical studies were performed to gain an understanding of the interaction of transient stress waves with steel bars in concrete structures containing surface-opening cracks. A reinforced concrete beam was constructed as an experimental specimen. The specimen was simply supported and loaded at the center point until cracks occurred. Experimental studies were carried out on the cracked beam. Two displacement receivers were placed on the opposite sides of a surface-opening crack to monitor disturbances caused by the arrivals of stress waves generated by impact. The first receiver and impact were located on the same side of the crack. The first receiver was used to trace the start rime of impact. The second one placed oil the opposite sine of the crack was used to find the arrival time of P-wave propagating through steel bars, and the arrival time of the diffracted P-wave from the bottom edge of the crack, Numerical and experimental results show: that rite presence of steel bars results in an initial disturbance in the waveform recorded by the second receiver because P-waves call propagate across the crack along the steel bars. it is also shown that the shortest travel path Soi a P-wave from the impact point through the steel bars to the second receiver is obtained if rile P-wave is incident upon the concrete/steel interface with a critical angle of incidence. Equations for determining rite depth of steel bars are presented. Because the amplitude of the initial disturbance caused by the steel bars is small, it is still easy to identify the following arrival of the P-wave diffracted from the bottom edge of the crack. Thus, the presence of steel reinforcing bars does not have a significant influence on measuring the crack depth

New technique based on stress waves for measuring cover thickness of closely spaced reinforcing bars

The objective of the research presented in this paper is to develop a new nondestructive test method to determine the cover thickness of reinforcing bars in concrete structures that contain closely arranged reinforcing bars. Even though the commercial covermeters based on magnetic and electrical methods are widely used in the detection of the depth and location of reinforcing bars, they are not suitable in the case of bars with small spacing. The technique proposed in this paper for detection of the closely arranged reinforcing bars makes use of stress waves. The conception of the new test scheme originated from the fact that the propagation of stress waves follows the shortest travel path dominated by the reinforcing bar under the test point and is not affected by adjacent reinforcing bars. Numerical studies were performed to investigate how the travel time of a P-wave propagating through reinforcing bars is changed as the test line is moved away from the axis of the reinforcing bars. Experimental studies were performed on concrete specimens that contain reinforcing bars with close spacing. Results obtained from numerical analysis show that when the test point is not exactly above the steel bar the travel time for a P-wave is increased with an increase in distance from the test line to the reinforcing bar Experimental results show that no matter how close the reinforcing bars are placed in concrete specimens, the cover thickness of the bars can be still measured accurately

Evaluation of bond quality at the interface between steel bar and concrete using the small-dimension break-off test

This paper investigates the feasibility of using the small-dimension break-off test for evaluation of the bond quality at the interface between steel bar and concrete. Experimental studies were performed on bar-type concrete specimens and reinforced concrete beams. Twelve bar-type concrete specimens containing plain and deformed steel bars with different diameters were used to develop the relationship between the break-off moment and the adhesive strength at the steel bar/concrete interface. Subsequently, three reinforced concrete beams containing normal reinforcing bars, epoxy-coated reinforcing bars, and bars smeared with oil to simulate various adhesive conditions at the bar/concrete interface were used to study how the break-off moment and the bond strength were affected by the different adhesive conditions. In addition, two beam specimens containing normal reinforcing bars were vibrated severely on a self-made shaking table shortly after initial setting of concrete to simulate the bond damage in fresh reinforced concrete beams due to unexpected vibration or impact. Experimental results show that the effective break-off moment has a good correlation with the adhesive strength at the interface between steel bar and concrete. The break-off moment increases with an increase in bond strength. It is demonstrated that the small-dimension break-off test is capable of evaluating damage at the steel bar/concrete interface

Cooperative Anchor-Free Position Estimation for Hierarchical Wireless Sensor Networks

This paper proposes a distributed algorithm for establishing connectivity and location estimation in cluster-based wireless sensor networks. The algorithm exploits the information flow while coping with distributed signal processing and the requirements of network scalability. Once the estimation procedure and communication protocol are performed, sensor clusters can be merged to establish a single global coordinate system without GPS sensors using only distance information. In order to adjust the sensor positions, the refinement schemes and cooperative fusion approaches are applied to reduce the estimation error and improve the measurement accuracy. This paper outlines the technical foundations of the localization techniques and presents the tradeoffs in algorithm design. The feasibility of the proposed schemes is shown to be effective under certain assumptions and the analysis is supported by simulation and numerical studies

Nondestructive evaluation of concrete quality and integrity in composite columns

This paper summarizes the results obtained from the studies aimed at determining the feasibility of using the impact-echo technique for nondestructive evaluation of concrete quality and integrity in composite columns. Both numerical and experimental studies are carried out to gain a thorough understanding of the transient impact response of composite columns with/without flaws. Results obtained from these studies show that the impact response of a solid composite column is composed of a number of cross-sectional modes of vibration generated by multiple wave reflections between close proximity of boundaries. The frequency of the fundamental mode can be used to determine the P-wave speed in concrete. The presence of flaws disrupts the spectral pattern associated with the solid case. A shift of the fundamental frequency to a lower value is the key to identifying the presence of a flaw. In addition, the spectrum will also show a high amplitude peak at the frequency corresponding to the depth of the flaw. (C) 1999 Elsevier Science Ltd. All rights reserved