32 research outputs found
Comparison of solar radiation pressure models for BDS IGSO and MEO satellites with emphasis on improving orbit quality
LUF7244 plus Dofetilide Rescues Aberrant Kv11.1 Trafficking and Produces Functional IKv11.1
Kv11.1 (hERG) channels play a critical role in repolarization of cardiomyocytes during the cardiac action potential (AP). Drug mediated Kv11.1 blockade results in AP prolongation, which poses an increased risk of sudden cardiac death. Many drugs, like pentamidine, interfere with normal Kv11.1 forward trafficking and thus reduce functional Kv11.1 channel densities. Although class III antiarrhythmics, e.g. dofetilide, rescue congenital and acquired forward trafficking defects, this is of little use due to their simultaneous acute channel blocking effect. We aimed to test the ability of a combination of dofetilide plus LUF7244, a Kv11.1 allosteric modulator/activator, to rescue Kv11.1 trafficking and produce functional Kv11.1 current. LUF7244 treatment by itself did not disturb or rescue WT or G601S Kv11.1 trafficking as shown by western blot and immunofluorescence microcopy analysis. Pentamidine-decreased maturation of WT Kv11.1 levels was rescued by 10 Ī¼M dofetilide or 10 Ī¼M dofetilide + 5 Ī¼M LUF7244. In trafficking defective G601S Kv11.1 cells, dofetilide (10 Ī¼M) or dofetilide+LUF7244 (10+5 Ī¼M) restored Kv11.1 trafficking also, as demonstrated by western blot and immunofluorescence microscopy. LUF7244 (10 Ī¼M) increased IKv11.1 despite the presence of dofetilide (1 Ī¼M) in WT Kv11.1 cells. In G601S expressing cells, long-term treatment (24-48 h) with LUF7244 (10 Ī¼M) and dofetilide (1 Ī¼M) increased IKv11.1 compared to non-treated, or acutely treated cells. We conclude that dofetilide plus LUF7244 rescues Kv11.1 trafficking and produces functional IKv11.1. Thus, combined administration of LUF7244 and an IKV11.1 trafficking corrector could serve as a new pharmacological therapy of both congenital and drug-induced Kv11.1 trafficking defects.Toxicolog
Improving BDS integer ambiguity resolution using satellite-induced code bias correction for precise orbit determination
Disease Associated Mutations in KIR Proteins Linked to Aberrant Inward Rectifier Channel Trafficking
The ubiquitously expressed family of inward rectifier potassium (KIR) channels, encoded by KCNJ genes, is primarily involved in cell excitability and potassium homeostasis. Channel mutations associate with a variety of severe human diseases and syndromes, affecting many organ systems including the central and peripheral neural system, heart, kidney, pancreas, and skeletal muscle. A number of mutations associate with altered ion channel expression at the plasma membrane, which might result from defective channel trafficking. Trafficking involves cellular processes that transport ion channels to and from their place of function. By alignment of all KIR channels, and depicting the trafficking associated mutations, three mutational hotspots were identified. One localized in the transmembrane-domain 1 and immediately adjacent sequences, one was found in the G-loop and Golgi-export domain, and the third one was detected at the immunoglobulin-like domain. Surprisingly, only few mutations were observed in experimentally determined Endoplasmic Reticulum (ER)exit-, export-, or ER-retention motifs. Structural mapping of the trafficking defect causing mutations provided a 3D framework, which indicates that trafficking deficient mutations form clusters. These "mutation clusters" affect trafficking by different mechanisms, including protein stability
Reducing influence of gravity model error in precise orbit determination of low Earth orbit satellites
Electrocatalytic redox neutral [3 + 2] annulation ofN-cyclopropylanilines and alkenes
Although synthetic organic electrochemistry (EC) has advanced significantly, net redox neutral electrosynthesis is quite rare. Two approaches have been employed to achieve this type of electrosynthesis. One relies on turnover of the product by the reactant in a chain mechanism. The other involves both oxidation on the anode and reduction on the cathode in which the radical cation or the radical anion of the product has to migrate between two electrodes. Herein, a home-built electrochemistry/mass spectrometry (EC/MS) platform was used to generate anN-cyclopropylaniline radical cation electrochemically and to monitor its reactivity toward alkenes by mass spectrometry (MS), which led to the discovery of a new redox neutral reaction of intermolecular [3 + 2] annulation ofN-cyclopropylanilines and alkenes to provide an aniline-substituted 5-membered carbocycleviadirect electrolysis (yield up to 81%). A chain mechanism, involving the regeneration of the substrate radical cation and the formation of the neutral product, is shown to be responsible for promoting such a redox neutral annulation reaction, as supported by experimental evidence of EC/MS
LUF7244, an allosteric modulator/activator of K v
Background and PurposeKv11.1 (hERG) channel blockade is an adverse effect of many drugs and lead compounds, associated with lethal cardiac arrhythmias. LUF7244 is a negative allosteric modulator/activator of Kv11.1 channels that inhibits early afterdepolarizations in vitro. We tested LUF7244 for antiarrhythmic efficacy and potential proarrhythmia in a dog model.Experimental ApproachLUF7244 was tested in vitro for (a) increasing human IKv11.1Ā and canine IKrĀ and (b) decreasing dofetilideāinduced action potential lengthening and early afterdepolarizations in cardiomyocytes derived from human induced pluripotent stem cells and canine isolated ventricular cardiomyocytes. In vivo, LUF7244 was given intravenously to anaesthetized dogs in sinus rhythm or with chronic atrioventricular block.Key ResultsLUF7244 (0.5ā10Ā Ī¼M) concentration dependently increased IKv11.1Ā by inhibiting inactivation. In vitro, LUF7244 (10Ā Ī¼M) had no effects on IKIR2.1, INav1.5, ICaāL, and IKs, doubled IKr, shortened human and canine action potential duration by approximately 50%, and inhibited dofetilideāinduced early afterdepolarizations. LUF7244 (2.5Ā mgĀ·kgā1Ā·15Ā minā1) in dogs with sinus rhythm was not proarrhythmic and shortened, nonāsignificantly, repolarization parameters (QTc: ā6.8%). In dogs with chronic atrioventricular block, LUF7244 prevented dofetilideāinduced torsades de pointes arrhythmias in 5/7 animals without normalization of the QTc. Peak LUF7244 plasma levels were 1.75Ā Ā±Ā 0.80 during sinus rhythm and 2.34Ā Ā±Ā 1.57Ā Ī¼M after chronic atrioventricular block.Conclusions and ImplicationsLUF7244 counteracted dofetilideāinduced early afterdepolarizations in vitro and torsades de pointes in vivo. Allosteric modulators/activators of Kv11.1 channels might neutralize adverse cardiac effects of existing drugs and newly developed compounds that display QTc lengthening.Pharmacolog