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Kcv channels from plant viruses represent the autonomous pore module of potassium channels, devoid of any regulatory domains. These small proteins show very reproducible single-channel behavior in planar lipid bilayers. Thus, they are an optimum system for the study of the biophysics of ion transport and gating. Structural models based on homology modeling have been used successfully, but experimental structural data are currently not available. Here we determine the size of the cytosolic pore entrance by studying the blocker kinetics. Blocker binding and dissociation rate constants ranging from 0.01 to 1000 ms -1 were determined for different quaternary ammonium ions. We found that the cytosolic pore entrance of Kcv NTS must be at least 11 Å wide. The results further indicate that the residues controlling a cytosolic gate in one of the Kcv isoforms influence blocker binding/dissociation as well as a second gate even when the cytosolic gate is in the open state. The voltage dependence of the rate constant of blocker release is used to test, which blockers bind to the same binding site.

Modulating the activity of ion channels by blockers yields information on both the mode of drug action and on the biophysics of ion transport. Here we investigate the interplay between ions in the selectivity filter (SF) of K + channels and the release kinetics of the blocker tetrapropylammonium in the model channel Kcv NTS . A quantitative expression calculates blocker release rate constants directly from voltage-dependent ion occupation probabilities in the SF. The latter are obtained by a kinetic model of single-channel currents recorded in the absence of the blocker. The resulting model contains only two adjustable parameters of ion-blocker interaction and holds for both symmetric and asymmetric ionic conditions. This data-derived model is corroborated by 3D reference interaction site model (3D RISM) calculations on several model systems, which show that the K + occupation probability is unaffected by the blocker, a direct consequence of the strength of the ion-carbonyl attraction in the SF, independent of the specific protein background. Hence, Kcv NTS channel blocker release kinetics can be reduced to a small number of system-specific parameters. The pore-independent asymmetric interplay between K + and blocker ions potentially allows for generalizing these results to similar potassium channels., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gabriel, Hansen, Urban, Drexler, Winterstein, Rauh, Thiel, Kast and Schroeder.)

Aim:  Segmental arterial mediolysis (SAM) is a rare non-atherosclerotic, non-inflammatory, non-infectious arteriopathy in middle-aged patients that tends to affect medium-sized splanchnic arteries typically leading to dissecting aneurysms which in case of rupture have a high mortality. Treatment options include watchful waiting and endovascular or surgical intervention. There are no official treatment guidelines and to the best of our knowledge, there has not been any report of extensive exclusion of multiple splanchnic vessel regions in affected patients to date., Materials and Methods:  We retrospectively examined the outcome of extensive splanchnic embolization in four patients suffering from SAM between 2011 and 2016 with follow-up periods of up to 7 years., Results:  One patient presented with abdominal pain due to rupture of aneurysms of the pancreaticoduodenal arcade, one with abdominal pain due to dissection, and two were clinically asymptomatic but displayed rapidly progressing disease over the course of 12 months. All patients were treated with complete exclusion of the diseased vessel segments by coiling all branches to and from the diseased segment. In three cases the main hepatic artery was excluded completely. In one case, the complete vascular bed of the celiac axis was excluded by coiling the distal vessel branches and placing a stent graft over the orifice of the celiac trunk. During a follow-up period of a minimum of 2 and a maximum of 7 years after intervention, there were no immediate or long-term complications except for a temporary arterio-portal fistula. Interestingly, no new diseased areas of SAM were detected afterwards., Conclusion:  Extensive endovascular exclusion of the entire diseased arterial segment with coils seems to be a safe and effective treatment option in patients with SAM presenting with ruptured or rapidly growing aneurysms. Provided that patients have normal liver function and proper portal venous flow, risk of hepatobiliary complications seems to be low even after extensive embolization., Key Points:   · An asymptomatic SAM can be followed up.. · In case of disease progression or suspicion of aneurysm rupture, an endovascular approach is indicated where the whole pathological vessel bed should be excluded with coils.. · It seems that exclusion of even extensive vessel areas is tolerated.., Citation Format: · Najafi A, Sheikh GT, Binkert C. Extensive Embolization of Splanchnic Artery Aneurysms due to Segmental Arterial Mediolysis. Fortschr Röntgenstr 2019; 191: 1010 - 1014., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alcohol group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compound 1 (RN486) ( J. Pharmacol. Exp. Ther. 2012 , 341 , 90 ), which was selected for advanced preclinical characterization based on its favorable properties.