The conduction pathway of potassium channels is water free under physiological conditions.

Ion conduction through potassium channels is a fundamental process of life. On the basis of crystallographic data, it was originally proposed that potassium ions and water molecules are transported through the selectivity filter in an alternating arrangement, suggesting a "water-mediated" knock-on mechanism. Later on, this view was challenged by results from molecular dynamics simulations that revealed a "direct" knock-on mechanism where ions are in direct contact. Using solid-state nuclear magnetic resonance techniques tailored to characterize the interaction between water molecules and the ion channel, we show here that the selectivity filter of a potassium channel is free of water under physiological conditions. Our results are fully consistent with the direct knock-on mechanism of ion conduction but contradict the previously proposed water-mediated knock-on mechanism

Direct detection of bound ammonium ions in the selectivity filter of ion channels by solid-state NMR.

The flow of ions across cell membranes facilitated by ion channels is an important function for all living cells. Despite the huge amount of structural data provided by crystallography, elucidating the exact interactions between the selectivity filter atoms and bound ions is challenging. Here, we detect bound 15 N-labeled ammonium ions as a mimic for potassium ions in ion channels using solid-state NMR under near-native conditions. The non-selective ion channel NaK showed two ammonium peaks corresponding to its two ion binding sites, while its potassium-selective mutant NaK2K that has a signature potassium- selective selectivity filter with four ion binding sites gave rise to four ammonium peaks. Ions bound in specific ion binding sites were identified based on magnetization transfer between the ions and carbon atoms in the selectivity filters. Magnetization transfer between bound ions and water molecules revealed that only one out of four ions in the selectivity filter of NaK2K is in close contact with water, which is in agreement with the direct knock-on ion conduction mechanism where ions are conducted through the channel by means of direct interactions without water molecules in between. Interestingly, the potassium-selective ion channels investigated here (NaK2K and, additionally, KcsA-Kv1.3) showed remarkably different chemical shifts for their bound ions, despite having identical amino acid sequences and crystal structures of their selectivity filters. Molecular dynamics simulations show similar ion binding and conduction behavior between ammonium and potassium ions and identify the origin of the differences between the investigated potassium channel

Superfluid Dynamics of a Bose-Einstein Condensate in a Periodic Potential

We investigate the superfluid properties of a Bose-Einstein condensate (BEC) trapped in a one dimensional periodic potential. We study, both analytically (in the tight binding limit) and numerically, the Bloch chemical potential, the Bloch energy and the Bogoliubov dispersion relation, and we introduce {\it two} different, density dependent, effective masses and group velocities. The Bogoliubov spectrum predicts the existence of sound waves, and the arising of energetic and dynamical instabilities at critical values of the BEC quasi-momentum which dramatically affect its coherence properties. We investigate the dependence of the dipole and Bloch oscillation frequencies in terms of an effective mass averaged over the density of the condensate. We illustrate our results with several animations obtained solving numerically the time-dependent Gross-Pitaevskii equation.Comment: 13 pages, 7 figures, movies and published paper available at http://www.iop.org/EJ/abstract/1367-2630/5/1/11

Multistable Solitons in the Cubic-Quintic Discrete Nonlinear Schr\"odinger Equation

We analyze the existence and stability of localized solutions in the one-dimensional discrete nonlinear Schr\"{o}dinger (DNLS) equation with a combination of competing self-focusing cubic and defocusing quintic onsite nonlinearities. We produce a stability diagram for different families of soliton solutions, that suggests the (co)existence of infinitely many branches of stable localized solutions. Bifurcations which occur with the increase of the coupling constant are studied in a numerical form. A variational approximation is developed for accurate prediction of the most fundamental and next-order solitons together with their bifurcations. Salient properties of the model, which distinguish it from the well-known cubic DNLS equation, are the existence of two different types of symmetric solitons and stable asymmetric soliton solutions that are found in narrow regions of the parameter space. The asymmetric solutions appear from and disappear back into the symmetric ones via loops of forward and backward pitchfork bifurcations.Comment: To appear Physica D. 23 pages, 13 figure

Structural studies suggest aggregation as one of the modes of action for teixobactin

Teixobactin is a new promising antibiotic that targets cell wall biosynthesis by binding to lipid II and has no detectable resistance thanks to its unique but yet not fully understood mechanism of operation. To aid in the structure-based design of teixobactin analogues with improved pharmacological properties, we present a 3D structure of native teixobactin in membrane mimetics and characterise its binding to lipid II through a combination of solution NMR and fast (90 kHz) magic angle spinning solid state NMR. In NMR titrations, we observe a pattern strongly suggesting interactions between the backbone of the C-terminal “cage” and the pyrophosphate moiety in lipid II. We find that the N-terminal part of teixobactin does not only act as a membrane anchor, as previously thought, but is actively involved in binding. Moreover, teixobactin forms a well-structured and specific complex with lipid II, where the N-terminal part of teixobactin assumes a b conformation that is highly prone to aggregation, which likely contributes to the antibiotic's high bactericidal efficiency. Overall, our study provides several new clues to teixobactin's modes of action

Multistable Solitons in Higher-Dimensional Cubic-Quintic Nonlinear Schroedinger Lattices

We study the existence, stability, and mobility of fundamental discrete solitons in two- and three-dimensional nonlinear Schroedinger lattices with a combination of cubic self-focusing and quintic self-defocusing onsite nonlinearities. Several species of stationary solutions are constructed, and bifurcations linking their families are investigated using parameter continuation starting from the anti-continuum limit, and also with the help of a variational approximation. In particular, a species of hybrid solitons, intermediate between the site- and bond-centered types of the localized states (with no counterpart in the 1D model), is analyzed in 2D and 3D lattices. We also discuss the mobility of multi-dimensional discrete solitons that can be set in motion by lending them kinetic energy exceeding the appropriately crafted Peierls-Nabarro barrier; however, they eventually come to a halt, due to radiation loss.Comment: 12 pages, 17 figure

Improved and standardized method for assessing years lived with disability after burns and its application to estimate the non-fatal burden of disease of burn injuries in Australia, New Zealand and the Netherlands

Background: Burden of disease estimates are an important resource in public health. Currently, robust estimates are not available for the burn population. Our objectives are to adapt a refined methodology (INTEGRIS method) to burns and to apply this new INTEGRIS-burns method to estimate, and compare, the burden of disease of burn injuries in Australia, New Zealand and the Netherlands. Methods: Existing European and Western-Australian health-related quality of life (HRQL) datasets were combined to derive disability weights for three homogenous burn injury groups based on percentage total body surface area (%TBSA) burned. Subsequently, incidence data from Australia, New Zealand, and the Netherlands from 2010 to 2017 were used to compute annual non-fatal burden of disease estimates for each of these three countries. Non-fatal burden of disease was measured by years lived w

The validity of the EQ-5D-3L items: An investigation with type 2 diabetes patients from six European countries

Background: Most previous studies concerning the validity of the EQ-5D-3L items refer to applications of only a single language version of the EQ-5D-3L in only one country. Therefore, there is little information concerning the extent to which the results can be generalised across different language versions and

Discovery of Highly Isoform Selective Orally Bioavailable Phosphoinositide 3-Kinase (PI3K)-γ Inhibitors

In this paper, we describe the discovery and optimization of a new chemotype of isoform selective PI3Kγ inhibitors. Starting from an HTS hit, potency and physicochemical properties could be improved to give compounds such as 15, which is a potent and remarkably selective PI3Kγ inhibitor with ADME properties suitable for oral administration. Compound 15 was advanced into in vivo studies showing dose-dependent inhibition of LPS-induced airway neutrophilia in rats when administered orally