Model-guided design of ligand-regulated RNAi for programmable control of gene expression

Progress in constructing biological networks will rely on the development of more advanced components that can be predictably modified to yield optimal system performance. We have engineered an RNA-based platform, which we call an shRNA switch, that provides for integrated ligand control of RNA interference (RNAi) by modular coupling of an aptamer, competing strand, and small hairpin (sh) RNA stem into a single component that links ligand concentration and target gene expression levels. A combined experimental and mathematical modelling approach identified multiple tuning strategies and moves towards a predictable framework for the forward design of shRNA switches. The utility of our platform is highlighted by the demonstration of fine-tuning, multi-input control, and model-guided design of shRNA switches with an optimized dynamic range. Thus, shRNA switches can serve as an advanced component for the construction of complex biological systems and offer a controlled means of activating RNAi in disease therapeutics

Innovation Dynamics, Best Practices, and Trends in the Off-Grid Clean Energy Market

n 2008, the authors of this article developed a “sector strategy” for the Global Social Benefit Incubator (GSBI) at Santa Clara University with the purpose of facilitating collaborative learning between BoP ventures, technology and business model innovation, and positive ecologies for cluster development. This article summarizes insights from the GSBI’s involvement with 60 ventures in the BoP clean energy sector

Innovation Dynamics, Best Practices, and Trends in the Off-Grid Clean Energy Market

En 2008, los autores de este artículo desarrollaron una “estrate- gia del sector” para la Global Social Benefit Incubator (GSBI) en la Santa Clara University, con el fin de facilitar el aprendizaje colaborativo entre las empresas de la base de la pirámide (BoP), la tecnología y la innovación del modelo de negocio, y las ecologías positivas para el desarrollo de clusters. Este artículo resume puntos de vista de la participación del GSBI con 60 empresas del sector de la energía limpia en la BoP.In 2008, the authors of this article developed a “sector strategy” for the Global Social Benefit Incubator (GSBI) at Santa Clara University with the purpose of facilitating collaborative learning between BoP ventures, technology and business model innovation, and positive ecologies for cluster development. This article summarizes insights from the GSBI’s involvement with 60 ventures in the BoP clean energy sector

DuMux 3 – an open-source simulator for solving flow and transport problems in porous media with a focus on model coupling

Authors: Timo Koch and Dennis Gläser and Kilian Weishaupt and Sina Ackermann and Martin Beck and Beatrix Becker and Samuel Burbulla and Holger Class and Edward Coltman and Simon Emmert and Thomas Fetzer and Christoph Grüninger and Katharina Heck and Johannes Hommel and Theresa Kurz and Melanie Lipp and Farid Mohammadi and Samuel Scherrer and Martin Schneider and Gabriele Seitz and Leopold Stadler and Martin Utz and Felix Weinhardt and Bernd Flemisc

Coupling of Smoothened to inhibitory G proteins reduces voltage-gated K

SMO (Smoothened), the central transducer of Hedgehog signaling, is coupled to heterotrimeric Gi proteins in many cell types, including cardiomyocytes. In this study, we report that activation of SMO with SHH (Sonic Hedgehog) or a small agonist, purmorphamine, rapidly causes a prolongation of the action potential duration that is sensitive to a SMO inhibitor. In contrast, neither of the SMO agonists prolonged the action potential in cardiomyocytes from transgenic GiCT/TTA mice, in which Gi signaling is impaired, suggesting that the effect of SMO is mediated by Gi proteins. Investigation of the mechanism underlying the change in action potential kinetics revealed that activation of SMO selectively reduces outward voltage-gated K+ repolarizing (Kv) currents in isolated cardiomyocytes and that it induces a down-regulation of membrane levels of Kv4.3 in cardiomyocytes and intact hearts from WT but not from GiCT/TTA mice. Moreover, perfusion of intact hearts with Shh or purmorphamine increased the ventricular repolarization time (QT interval) and induced ventricular arrhythmias. Our data constitute the first report that acute, noncanonical Hh signaling mediated by Gi proteins regulates K+ currents density in cardiomyocytes and sensitizes the heart to the development of ventricular arrhythmias. © 2018 Cheng et al

On the Calibration of a Size-Structured Population Model from Experimental Data

The aim of this work is twofold. First, we survey the techniques developed in (Perthame, Zubelli, 2007) and (Doumic, Perthame, Zubelli, 2008) to reconstruct the division (birth) rate from the cell volume distribution data in certain structured population models. Secondly, we implement such techniques on experimental cell volume distributions available in the literature so as to validate the theoretical and numerical results. As a proof of concept, we use the data reported in the classical work of Kubitschek [3] concerning Escherichia coli in vitro experiments measured by means of a Coulter transducer-multichannel analyzer system (Coulter Electronics, Inc., Hialeah, Fla, USA.) Despite the rather old measurement technology, the reconstructed division rates still display potentially useful biological features

Pharmacokinetic Characterisation and Comparison of Bioavailability of Intranasal Fentanyl, Transmucosal, and Intravenous Administration through a Three-Way Crossover Study in 24 Healthy Volunteers

Background. For more than 60 years, the synthetic opioid fentanyl has been widely used in anaesthesia and analgesia. While the intravenous formulation is primarily used for general anaesthesia and intensive care settings, the drug’s high lipophilic properties also allow various noninvasive routes of administration. Published data suggest that intranasal administration is also attractive for use as intranasal patient-controlled analgesia (PCA). A newly developed intranasal fentanyl formulation containing 47 μg fentanyl, intravenous fentanyl, and oral transmucosal fentanyl citrate were characterised, and bioavailability was compared to assess the suitability of the intranasal formulation for an intranasal PCA product. Methods. 27 healthy volunteers were enrolled in a single-centre, open-label, randomised (order of treatments), single-dose study in a three-period crossover design. The pharmacokinetics of one intranasal puff of fentanyl formulation (47 μg, 140 mL per puff), one short intravenous infusion of 50 μg fentanyl, and one lozenge with an integrated applicator (200 μg fentanyl) were studied, and bioavailability was calculated. Blood samples were collected over 12 hours, and plasma concentrations of fentanyl were determined by HPLC with MS/MS detection. Results. 24 volunteers completed the study. The geometric mean of AUC0-tlast was the highest with oral transmucosal administration (1106 h  pg/ml, CV% = 32.86), followed by intravenous (672 h  pg/ml, CV% = 32.18) and intranasal administration (515 h  pg/ml, CV% = 30.10). Cmax was 886 pg/ml (CV% = 59.38) for intravenous, 338 pg/ml (CV% = 45.61) for intranasal, and 310 pg/ml (CV% = 29.58) for oral transmucosal administration. tmax was shortest for intravenous administration (0.06 h, SD = 0.056), followed by intranasal (0.21 h, SD = 0.078) and oral transmucosal administration (1.20 h, SD = 0.763). Dose-adjusted absolute bioavailability was determined to be 74.70% for the intranasal formulation and 41.25% for the oral transmucosal product. In total, 38 adverse events (AEs) occurred. Fourteen AEs were potentially related to the investigational items. No serious AE occurred. Conclusion. Pharmacokinetic parameters and bioavailability of the investigated intranasal fentanyl indicated suitability for its intended use as an intranasal PCA option