Upscaling and automation of electrophysiology: toward high throughput screening in ion channel drug discovery

Effective screening of large compound libraries in ion channel drug discovery requires the development of new electrophysiological techniques with substantially increased throughputs compared to the conventional patch clamp technique. Sophion Bioscience is aiming to meet this challenge by developing two lines of automated patch clamp products, a traditional pipette-based system called Apatchi-1, and a silicon chip-based system QPatch. The degree of automation spans from semi-automation (Apatchi-1) where a trained technician interacts with the system in a limited way, to a complete automation (QPatch 96) where the system works continuously and unattended until screening of a full compound library is completed. The performance of the systems range from medium to high throughputs.     

A Strategy for Rapid Mismatch Evaluation of Transient Characteristics of CMOS Analog Cells

A strategy is presented to evaluate the statistical means and standard deviations of the transient characteristics of CMOS analog cells. Based upon the Monte Carlo analysis of electrical simulations, this strategy follows a circuit-theory based approach achieving an important reduction on matrix ranges and consequently on the number of operations involved in the resolution of the circuit. The CPU time-consuming reduction is achieved also by saving information corresponding to the nominal transient analysis. We include comparative results for several CMOS cells showing the advantages of the proposed strategy.     

Quadrature ���� Modulators for Cognitive Radio��I/Q Imbalance Analysis and Complex Multiband Principle

This article discusses the applicability of quadrature ΣΔ modulator (QΣΔM) based analog-to-digital (A/D) conversion in cognitive radio (CR) receivers. First, unavoidable in-phase/quadrature (I/Q) mismatch effects, limiting the dynamic range, are analyzed in closed-form in the case of a first-order modulator. In addition, using the derived analytical converter model, it is shown that notching the signal transfer function (STF) of the modulator at the mirror frequencies of the desired signals will effectively cancel the I/Q imbalance induced mirror-frequency interference in case of the modulator feedback mismatch. In practice, such STF design is easy to implement within the existing converter circuitry, as will be demonstrated in this article. The latter part of the article proposes a novel complex multiband QΣΔM scheme, particularly aimed for the CR receivers. This multiband scheme allows parallel reception of scattered frequency chunks in the CR context and is stemming from the additional degrees of freedom in noise transfer function (NTF) design, provided by the QΣΔM principle. Here multiple noise shaping notches on distinct frequencies are effectively realized through proper design of complex NTF. The modulator structure also allows flexible reconfigurability of the notches with straightforward parameterization of the modulator transfer functions. When combined with the above mirror-frequency rejecting STF design, the concept is demonstrated and proved effective and robust against I/Q imbalances using practical radio signal simulations in realistic received signal conditions.     

Electronic Granularity and the Work Function of Transparent Conducting ZnO:Al Thin Films

Controlling the efficiency of electron transport across oxide interfaces is essential for numerous emerging technologies including advanced photovoltaics and light emitting devices. This work illuminates the connections between granular structure, defect chemistry, and the work function of a technologically important transparent conductor, ZnO:Al. Visual evidence is provided for a model of grain boundary oxidation in the form of nanometer‐scale heterogeneity in the contact potential between grains and grain boundaries, a phenomenon referred to as electronic granularity. By correlating scanning probe data with photoemission spectroscopy we relate electronic granularity to defect chemistry and, importantly, account for the overall trends in work function. The resulting physical picture connects heterogeneity at the nanoscale to macroscopic properties, informs the design of transparent electrodes, and may be broadly relevant to granular oxide conductors.     

Software‐defined network‐based prioritization to avoid video freezes in HTTP adaptive streaming

HTTP adaptive streaming (HAS) is becoming the de facto standard for video streaming services over the Internet. In HAS, each video is segmented and stored in different qualities. Rate adaptation heuristics, deployed at the client, allow the most appropriate quality level to be dynamically requested, based on the current network conditions. It has been shown that state‐of‐the‐art heuristics perform suboptimal when sudden bandwidth drops occur, therefore leading to freezes in the video playout, the main factor influencing users' quality of experience (QoE). This issue is aggravated in case of live events, where the client‐side buffer has to be kept as small as possible in order to reduce the playout delay between the user and the live signal. In this article, we propose a framework capable of increasing the QoE of HAS clients by reducing video freezes. The framework is based on OpenFlow, a widely adopted protocol to implement the software‐defined networking principle. An OpenFlow controller is in charge of introducing prioritized delivery of HAS segments, based on the network conditions and the HAS clients' status. Particularly, the HAS clients' status is obtained without any explicit clients‐to‐controller communication, and thus, no extra signaling is introduced into the network. Moreover, this OpenFlow controller is transparent to the quality decision process of the clients, as it assists the delivery of the segments, but it does not determine the actual quality to be requested. In order to provide a comprehensive analysis of the proposed approach, we investigate the performance of the proposed OpenFlow‐based framework in the presence of realistic Internet cross‐traffic. Particularly, we model two types of applications, namely, HTTP web browsing and progressive download video streaming, which currently represent the majority of Internet traffic together with HAS. By evaluating this novel approach through emulation in several multi‐client scenarios, we show how the proposed approach can reduce freeze time for the HAS clients due to network congestion up to 10 times compared with state‐of‐the‐art heuristics, without impacting the performance of the cross‐traffic applications. Copyright © 2016 John Wiley & Sons, Ltd.     

New Drug‐Structure‐Directing Agent Concept: Inherent Pharmacological Activity Combined with Templating Solid and Hollow‐Shell Mesostructured Silica Nanoparticles

One of the major challenges in medicine is the delivery and control of drug release over time. Current approaches take advantage of mesostructured silica nanoparticles (MSNs) as carriers but suffer several problems including complex synthesis that requires sequential steps for (1) removal of surfactants and (2) functionalization of MSNs to allow upload of the drugs. Here, a novel solution is presented to these restrictions: the design of drug‐structure‐directing agents (DSDAs) with dual inherent pharmacological activity and ability to direct the formation of solid and hollow‐shell MSNs. Pharmacologically active DSDAs obtained by amidation of drugs with fatty acids are allowed to form micelles, around which the inorganic species self‐assembled to form MSNs. Since the DSDAs direct the formation of MSNs, the steps to remove surfactants, functionalization, and drug upload are not required. The MSNs thus prepared provide sustained release of the drug over more than six months, as well as rapid cellular internalization by both physiological and tumoral human colon cells without affecting cell viability. Moreover, the gradual intracellular release of both, the active drug and lipid moiety with potential nutraceutical properties is proved. MSN particles designed with this approach are promising vehicles for controlled and sustained intra‐or extracellular drug‐delivery.     

Amino acid composition of wheat grain. 1: Changes during development

The changes in the composition of free and total amino acids in wheat grain during development are described: the experiment was performed in a growth chamber with three varieties of winter wheat (Triticum aestivum L.): Splendeur, Hobbit and Maris Huntsman. The changes in the total composition of amino acids of the grain as development progressed were consistent with an increase in the proportion of storage proteins. At 15 days after anthesis, the relative amount of glycine increased, suggesting that at this moment the proportion of gliadins was relatively low. The relative amount of arginine increased in mature grain, showing that at times close to maturity the relative proportion of synthesis of a protein fraction rich in this amino acid increased. Free glutamate, proline and arginine decreased at 15 days to a greater extent than the other amino acids and was present in low relative amounts during the period of maximum protein synthesis in the grain; these three amino acids could be the most limiting for protein synthesis in grain. In the free fraction the following showed a similar pattern of change during grain development: aspartate, arginine and histidine on the one hand, and on the other alanine, valine, leucine, isoleucine, threonine, phenylalanine and tyrosine; moreover both groups were inversely correlated. Glycine and lysine were directly related to each other and inversely to glutamate.     

Effect of the Twisting Motion on the Nonunifornities of Transmyocardial Fiber Mechanics and Energy Demand A Theoretical Study

The contraction of the left ventricle (LV) is manifested by a distribution of strains and strain rates throughout the muscle thickness. Using a nested shell spheroidal model of the LV, which accounts for a fiber angle distribution from + 60°at the endocardium to ?60° at the epicardium, and the radial electrical activation pattern from the endocardium to the epicardium, it can be shown that endocardial layers undergo higher strains than the epicardial layers throughout the cardiac cycle, and higher length changes characterize the endocardial sarcomeres relative to the epicardial sarcomeres. However, the calculated nonuniformities in the sarcomeres' shortening are significantly moderated when the physiological twisting motion of the LV around the longitudinal axis is accounted for. Thus, the twisting motion of the heart is a basic mechanism by which the sarcomere function is maintained within its physiological range.