Recent advances in our understanding of the structure and function of more unusual cation channels.

As their name implies, cation channels allow the regulated flow of cations such as sodium, potassium, calcium, and magnesium across cellular and intracellular membranes. Cation channels have long been known for their fundamental roles in controlling membrane potential and excitability in neurons and muscle. In this review, we provide an update on the recent advances in our understanding of the structure-function relationship and the physiological and pathophysiological role of cation channels. The most exciting developments in the last two years, in our opinion, have been the insights that cryoelectron microscopy has provided into the inner life and the gating of not only voltage-gated channels but also mechanosensitive and calcium- or sodium-activated channels. The mechanosensitive Piezo channels especially have delighted the field not only with a fascinating new type of structure but with important roles in blood pressure regulation and lung function

Probing the atmosphere of a sub-Jovian planet orbiting a cool dwarf

We derive the 0.01 $\mu$m binned transmission spectrum, between 0.74 and 1.0 $\mu$m, of WASP-80b from low resolution spectra obtained with the FORS2 instrument attached to ESO's Very Large Telescope. The combination of the fact that WASP-80 is an active star, together with instrumental and telluric factors, introduces correlated noise in the observed transit light curves, which we treat quantitatively using Gaussian Processes. Comparison of our results together with those from previous studies, to theoretically calculated models reveals an equilibrium temperature in agreement with the previously measured value of 825K, and a sub-solar metallicity, as well as an atmosphere depleted of molecular species with absorption bands in the IR ($\gg 5\sigma$). Our transmission spectrum alone shows evidence for additional absorption from the potassium core and wing, whereby its presence is detected from analysis of narrow 0.003 $\mu$m bin light curves ($\gg 5\sigma$). Further observations with visible and near-UV filters will be required to expand this spectrum and provide more in-depth knowledge of the atmosphere. These detections are only made possible through an instrument-dependent baseline model and a careful analysis of systematics in the data.Comment: 13 pages, 11 figures, 3 tables. Accepted for publication in MNRA

The Trials and Tribulations of Structure Assisted Design of KCa Channel Activators.

Calcium-activated K+ channels constitute attractive targets for the treatment of neurological and cardiovascular diseases. To explain why certain 2-aminobenzothiazole/oxazole-type KCa activators (SKAs) are KCa3.1 selective we previously generated homology models of the C-terminal calmodulin-binding domain (CaM-BD) of KCa3.1 and KCa2.3 in complex with CaM using Rosetta modeling software. We here attempted to employ this atomistic level understanding of KCa activator binding to switch selectivity around and design KCa2.2 selective activators as potential anticonvulsants. In this structure-based drug design approach we used RosettaLigand docking and carefully compared the binding poses of various SKA compounds in the KCa2.2 and KCa3.1 CaM-BD/CaM interface pocket. Based on differences between residues in the KCa2.2 and KCa.3.1 models we virtually designed 168 new SKA compounds. The compounds that were predicted to be both potent and KCa2.2 selective were synthesized, and their activity and selectivity tested by manual or automated electrophysiology. However, we failed to identify any KCa2.2 selective compounds. Based on the full-length KCa3.1 structure it was recently demonstrated that the C-terminal crystal dimer was an artefact and suggested that the "real" binding pocket for the KCa activators is located at the S4-S5 linker. We here confirmed this structural hypothesis through mutagenesis and now offer a new, corrected binding site model for the SKA-type KCa channel activators. SKA-111 (5-methylnaphtho[1,2-d]thiazol-2-amine) is binding in the interface between the CaM N-lobe and the S4-S5 linker where it makes van der Waals contacts with S181 and L185 in the S45A helix of KCa3.1

Entrepreneurship in public administration and public policy programs in Germany and the United States

The following contribution hypothesizes that it is crucial for future professionals in public administrations and organizations to be familiar with the concepts, tools, and techniques of policy, public, and social entrepreneurship to address societal, environmental, health, and wicked problems in an innovative and sustainable way. Attention is drawn to the importance of entrepreneurship as an essential asset and feature of public administration and public policy education at higher educational institutions in Germany and the United States. The paper aims at filling a research gap because knowledge about the interrelationships between entrepreneurship and public administration and public policy education is still underdeveloped. Emphasis is put on the discussion why entrepreneurship should be incorporated in curricula and how study programs have been designed or reformed, while placing emphasis on entrepreneurship in meeting current and complex challenges in the public sector. Findings from a systematic online assessment are presented which show whether and how policy, public and social entrepreneurship are taught as an integral element of current governance and public policy study programs and what difference it makes teaching and learning wise. The findings reflect a high demand for entrepreneurship education by public administration and public policy students, on the one hand, and a low incorporation in curricula, on the other hand. Two case studies from Germany and the United States are presented which serve as good practice examples on how to transfer public, policy, and social entrepreneurship into curricula

Alpha1 -adrenergic stimulation selectively enhances endothelium-mediated vasodilation in rat cremaster arteries.

We have systematically investigated how vascular smooth muscle α1 -adrenoceptor activation impacts endothelium-mediated vasodilation in isolated, myogenically active, rat cremaster muscle 1A arteries. Cannulated cremaster arteries were pressurized intraluminally to 70 mmHg to induce myogenic tone, and exposed to vasoactive agents via bath superfusion at 34°C. Smooth muscle membrane potential was measured via sharp microelectrode recordings in pressurized, myogenic arteries. The α1 -adrenergic agonist phenylephrine (25-100 nmol/L) produced further constriction of myogenic arteries, but did not alter the vasorelaxant responses to acetylcholine (0.3 μmol/L), SKA-31 (an activator of endothelial Ca2+ -dependent K+ channels) (3 μmol/L) or sodium nitroprusside (10 μmol/L). Exposure to 0.25-1 μmol/L phenylephrine or 1 μmol/L norepinephrine generated more robust constrictions, and also enhanced the vasodilations evoked by acetylcholine and SKA-31, but not by sodium nitroprusside. In contrast, the thromboxane receptor agonist U46619 (250 nmol/L) dampened responses to all three vasodilators. Phenylephrine exposure depolarized myogenic arteries, and mimicking this effect with 4-aminopyridine (1 mmol/L) was sufficient to augment the SKA-31-evoked vasodilation. Inhibition of L-type Ca2+ channels by 1 μmol/L nifedipine decreased myogenic tone, phenylephrine-induced constriction and prevented α1 -adrenergic enhancement of endothelium-evoked vasodilation; these latter deficits were overcome by exposure to 3 and 10 μmol/L phenylephrine. Mechanistically, augmentation of ACh-evoked dilation by phenylephrine was dampened by eNOS inhibition and abolished by blockade of endothelial KCa channels. Collectively, these data suggest that increasing α1 -adrenoceptor activation beyond a threshold level augments endothelium-evoked vasodilation, likely by triggering transcellular signaling between smooth muscle and the endothelium. Physiologically, this negative feedback process may serve as a "brake" to limit the extent of vasoconstriction in the skeletal microcirculation evoked by the elevated sympathetic tone

Introduction:Toward More Inclusive and Comparative Perspectives in the Histories of Geographical Knowledge

This is an Accepted Manuscript of an article published by Taylor & Francis in The Professional Geographer on 17 March 2017, available online: http://www.tandfonline.com/10.1080/00330124.2017.1288572