Drug Repurposing: The Anthelmintics Niclosamide and Nitazoxanide Are Potent TMEM16A Antagonists That Fully Bronchodilate Airways

There is an unmet need in severe asthma where approximately 40% of patients exhibit poor β-agonist responsiveness, suffer daily symptoms and show frequent exacerbations. Antagonists of the Ca2+-activated Cl− channel, TMEM16A, offers a new mechanism to bronchodilate airways and block the multiple contractiles operating in severe disease. To identify TMEM16A antagonists we screened a library of ∼580,000 compounds. The anthelmintics niclosamide, nitazoxanide, and related compounds were identified as potent TMEM16A antagonists that blocked airway smooth muscle depolarization and contraction. To evaluate whether TMEM16A antagonists resist use- and inflammatory-desensitization pathways limiting β-agonist action, we tested their efficacy under harsh conditions using maximally contracted airways or airways pretreated with a cytokine cocktail. Stunningly, TMEM16A antagonists fully bronchodilated airways, while the β-agonist isoproterenol showed only partial effects. Thus, antagonists of TMEM16A and repositioning of niclosamide and nitazoxanide represent an important additional treatment for patients with severe asthma and COPD that is poorly controlled with existing therapies. It is of note that drug repurposing has also attracted wide interest in niclosamide and nitazoxanide as a new treatment for cancer and infectious disease. For the first time we identify TMEM16A as a molecular target for these drugs and thus provide fresh insights into their mechanism for the treatment of these disorders in addition to respiratory disease

Development of an Experimental Demonstrator Unit Using Nitrous Oxide/Ethylene Premixed Bipropellant for Satellite Applications

In the continuously growing scientific area and market of satellite propulsion systems, the need for replacement of toxic propellants like Hydrazine with human- and environment-friendlier substances called Green Propellants has arisen. Within the context of this research initiative and in terms with the REACH-Regulation, the German Aerospace Center (DLR) in Lampoldshausen is developing and testing an experimental demonstrator based on the technology of Nitrous Oxide Fuel Blends, which involve the mixture of Dinitrogenmonoxide with Carbon Hydrides. Specifically, at the testing facility of M11, the combination of Nitrous Oxide (N2O) and Ethylene (C2H4) as a premixed Bipropellant for applications in satellite propulsion modules is being examined. The combination of a high specific impulse (320s at 10 bar, ε=40 against vacuum) with the classic advantages of lighter feed and storage systems connected to monopropellants, render the mixture a strong candidate for usage as a green propellant in satellite applications. Within this project, the development of different injection systems has taken place, in order to examine the combustion properties of the propellant in different phases (gas or liquid) and in different mass flow rate regimes. By taking into consideration the two phase flows present in satellite thruster firings due to the injection against vacuum, the tests ran so far involve a gaseous mixture. Since the outlook of the project aims for a liquid storage and injection of the propellant, a simulation tool describing the necessary conditions for the phase change (condensation or evaporation) was also generated. The absence of accurate experimental data for the state of the mixture in the 2 phase region renders the simulation a preliminary tool of the design of the mixture’s liquefaction facility. Further CFD Simulations in combination with experimental tests for the full description of the combustion properties and the mixture’s physical characteristics in gaseous and liquid phase are planned for the future

Test Facilities to Assess Properties of a Nitrous Oxide/Ethene Premixed Bipropellant for Satellite Propulsion System

Attitude an orbit control in today´s satelite propulsion system are mostly realized with Hydrazine as a Monopropellant. Due to its toxicity and the carcinogenic effect on the human body it is difficult to handle and applications run by Hydrazine will be restricted by the REACH-Regulation in the future. Hence, there is a growing demand for more environmentally friendly propellants, so called "Green Propellants" Requirements are a low toxicity while preserving a high l. Lower costs are one side effect thanks to an easier propellant handling, e.g. fueling

Transcription of histone gene cluster by differential core-promoter factors

The 100 copies of tandemly arrayed Drosophila linker (H1) and core (H2A/B and H3/H4) histone gene cluster are coordinately regulated during the cell cycle. However, the molecular mechanisms that must allow differential transcription of linker versus core histones prevalent during development remain elusive. Here, we used fluorescence imaging, biochemistry, and genetics to show that TBP (TATA-box-binding protein)-related factor 2 (TRF2) selectively regulates the TATA-less Histone H1 gene promoter, while TBP/TFIID targets core histone transcription. Importantly, TRF2-depleted polytene chromosomes display severe chromosomal structural defects. This selective usage of TRF2 and TBP provides a novel mechanism to differentially direct transcription within the histone cluster. Moreover, genome-wide chromatin immunoprecipitation (ChIP)-on-chip analyses coupled with RNA interference (RNAi)-mediated functional studies revealed that TRF2 targets several classes of TATA-less promoters of >1000 genes including those driving transcription of essential chromatin organization and protein synthesis genes. Our studies establish that TRF2 promoter recognition complexes play a significantly more central role in governing metazoan transcription than previously appreciated

The RSC chromatin remodelling enzyme has a unique role in directing the accurate positioning of nucleosomes

The molecular mechanisms involved in establishing nucleosome positions in vivo are not well understood. Here, RSC is specifically required for moving nucleosomes from their intrinsically preferred in vitro reconstituted locations to their physiologically relevant positions