Drug Discovery for Duchenne Muscular Dystrophy via Utrophin Promoter Activation Screening

Background: Duchenne muscular dystrophy (DMD) is a devastating muscle wasting disease caused by mutations in dystrophin, a muscle cytoskeletal protein. Utrophin is a homologue of dystrophin that can functionally compensate for its absence when expressed at increased levels in the myofibre, as shown by studies in dystrophin-deficient mice. Utrophin upregulation is therefore a promising therapeutic approach for DMD. The use of a small, drug-like molecule to achieve utrophin upregulation offers obvious advantages in terms of delivery and bioavailability. Furthermore, much of the time and expense involved in the development of a new drug can be eliminated by screening molecules that are already approved for clinical use. Methodology/Principal Findings: We developed and validated a cell-based, high-throughput screening assay for utrophin promoter activation, and used it to screen the Prestwick Chemical Library of marketed drugs and natural compounds. Initial screening produced 20 hit molecules, 14 of which exhibited dose-dependent activation of the utrophin promoter and were confirmed as hits. Independent validation demonstrated that one of these compounds, nabumetone, is able to upregulate endogenous utrophin mRNA and protein, in C2C12 muscle cells. Conclusions/Significance: We have developed a cell-based, high-throughput screening utrophin promoter assay. Using this assay, we identified and validated a utrophin promoter-activating drug, nabumetone, for which pharmacokinetics an

Printing Technologies for Integration of Electronic Devices and Sensors

Many different methods, such as screen printing, gravure, flexography, inkjet etc., have been employed to print electronic devices. Depending on the type and performance of the devices, processing is done at low or high temperature using precursor- or particle-based inks. As a result of the processing details, devices can be fabricated on flexible or non-flexible substrates, depending on their temperature stability. Furthermore, in order to reduce the operating voltage, printed devices rely on high-capacitance electrolytes rather than on dielectrics. The printing resolution and speed are two of the major challenging parameters for printed electronics. High-resolution printing produces small-size printed devices and high-integration densities with minimum materials consumption. However, most printing methods have resolutions between 20 and 50 μm. Printing resolutions close to 1 μm have also been achieved with optimized process conditions and better printing technology. The final physical dimensions of the devices pose severe limitations on their performance. For example, the channel lengths being of this dimension affect the operating frequency of the thin-film transistors (TFTs), which is inversely proportional to the square of channel length. Consequently, short channels are favorable not only for high-frequency applications but also for high-density integration. The need to reduce this dimension to substantially smaller sizes than those possible with today’s printers can be fulfilled either by developing alternative printing or stamping techniques, or alternative transistor geometries. The development of a polymer pen lithography technique allows scaling up parallel printing of a large number of devices in one step, including the successive printing of different materials. The introduction of an alternative transistor geometry, namely the vertical Field Effect Transistor (vFET), is based on the idea to use the film thickness as the channel length, instead of the lateral dimensions of the printed structure, thus reducing the channel length by orders of magnitude. The improvements in printing technologies and the possibilities offered by nanotechnological approaches can result in unprecedented opportunities for the Internet of Things (IoT) and many other applications. The vision of printing functional materials, and not only colors as in conventional paper printing, is attractive to many researchers and industries because of the added opportunities when using flexible substrates such as polymers and textiles. Additionally, the reduction of costs opens new markets. The range of processing techniques covers laterally-structured and large-area printing technologies, thermal, laser and UV-annealing, as well as bonding techniques, etc. Materials, such as conducting, semiconducting, dielectric and sensing materials, rigid and flexible substrates, protective coating, organic, inorganic and polymeric substances, energy conversion and energy storage materials constitute an enormous challenge in their integration into complex devices