Nature of the magnetic stripes in fully oxygenated La2CuO 4 y

We present triple axis neutron scattering studies of static and dynamic magnetic stripes in an optimally oxygen doped cuprate superconductor, La2CuO4 y, which exhibits a clean superconducting transition at Tc 42K. Polarization analysis reveals that the magnetic stripe structure is equally represented along both of the tetragonal crystal axes and that the fluctuating stripes display significant weight for in plane as well as out of plane spin components. Both static magnetic order as well as low energy fluctuations are fully developed in zero applied magnetic field and the low energy spin fluctuations at amp; 8463; amp; 969; 0.3 10meV intensify on cooling. We interpret this as an indication that superconductivity and low energy spin fluctuations coexist microscopically in spatial regions which are separated from domains with static magnetic orde

Influence of ischemic core muscle fibers on surface depolarization potentials in superfused cardiac tissue preparations: a simulation study

Thin-walled cardiac tissue samples superfused with oxygenated solutions are widely used in experimental studies. However, due to decreased oxygen supply and insufficient wash out of waste products in the inner layers of such preparations, electrophysiological functions could be compromised. Although the cascade of events triggered by cutting off perfusion is well known, it remains unclear as to which degree electrophysiological function in viable surface layers is affected by pathological processes occurring in adjacent tissue. Using a 3D numerical bidomain model, we aim to quantify the impact of superfusion-induced heterogeneities occurring in the depth of the tissue on impulse propagation in superficial layers. Simulations demonstrated that both the pattern of activation as well as the distribution of extracellular potentials close to the surface remain essentially unchanged. This was true also for the electrophysiological properties of cells in the surface layer, where most relevant depolarization parameters varied by less than 5.5 %. The main observed effect on the surface was related to action potential duration that shortened noticeably by 53 % as hypoxia deteriorated. Despite the known limitations of such experimental methods, we conclude that superfusion is adequate for studying impulse propagation and depolarization whereas repolarization studies should consider the influence of pathological processes taking place at the core of tissue sample

Cryo-EM structure of the complete and ligand-saturated insulin receptor ectodomain

Glucose homeostasis and growth essentially depend on the hormone insulin engaging its receptor. Despite biochemical and structural advances, a fundamental contradiction has persisted in the current understanding of insulin ligand-receptor interactions. While biochemistry predicts two distinct insulin binding sites, 1 and 2, recent structural analyses have resolved only site 1. Using a combined approach of cryo-EM and atomistic molecular dynamics simulation, we present the structure of the entire dimeric insulin receptor ectodomain saturated with four insulin molecules. Complementing the previously described insulin-site 1 interaction, we present the first view of insulin bound to the discrete insulin receptor site 2. Insulin binding stabilizes the receptor ectodomain in a T-shaped conformation wherein the membrane-proximal domains converge and contact each other. These findings expand the current models of insulin binding to its receptor and of its regulation. In summary, we provide the structural basis for a comprehensive description of ligand-receptor interactions that ultimately will inform new approaches to structure-based drug design.Peer reviewe

ATP release via anion channels

ATP serves not only as an energy source for all cell types but as an ‘extracellular messenger-for autocrine and paracrine signalling. It is released from the cell via several different purinergic signal efflux pathways. ATP and its Mg2+ and/or H+ salts exist in anionic forms at physiological pH and may exit cells via some anion channel if the pore physically permits this. In this review we survey experimental data providing evidence for and against the release of ATP through anion channels. CFTR has long been considered a probable pathway for ATP release in airway epithelium and other types of cells expressing this protein, although non-CFTR ATP currents have also been observed. Volume-sensitive outwardly rectifying (VSOR) chloride channels are found in virtually all cell types and can physically accommodate or even permeate ATP4- in certain experimental conditions. However, pharmacological studies are controversial and argue against the actual involvement of the VSOR channel in significant release of ATP. A large-conductance anion channel whose open probability exhibits a bell-shaped voltage dependence is also ubiquitously expressed and represents a putative pathway for ATP release. This channel, called a maxi-anion channel, has a wide nanoscopic pore suitable for nucleotide transport and possesses an ATP-binding site in the middle of the pore lumen to facilitate the passage of the nucleotide. The maxi-anion channel conducts ATP and displays a pharmacological profile similar to that of ATP release in response to osmotic, ischemic, hypoxic and salt stresses. The relation of some other channels and transporters to the regulated release of ATP is also discussed

The mechanisms of sarcoplasmic reticulum Ca2+ release in toad pacemaker cells

The mechanisms of sarcoplasmic reticulum (SR) Ca2+ release in pacemaker cells from the sinus venosus of the cane toad (Bufo marinus) were studied. Single, isolated cells were voltage clamped using a nystatin-perforated patch. Ionic currents and intracellular Ca2+ concentration ([Ca2+]i) were recorded simultaneously.Depolarizations of 300 ms duration from a holding potential of −55 mV produced an inward current which had a bell-shaped relationship with voltage. Inward current first appeared at about −45 mV, reached a maximum of −343 ± 46 pA at −15 mV and reversed at +45 mV. In contrast the amplitude of the increase in [Ca2+]i caused by depolarization (Ca2+ transient) increased monotonically with the increasing depolarization. At −15 mV the amplitude of the Ca2+ transient was 243 ± 33 nm and at +45 mV it was 411 ± 43 nm.The inward current produced by depolarizations to −5 mV was largely eliminated by the L-type Ca2+ channel blocker nifedipine (10 μM) while 37 ± 7% of the Ca2+ transient persisted. A significantly larger proportion of the Ca2+ transient (56 ± 5%) remained at +85 mV in the presence of nifedipine.The SR Ca2+ pump inhibitor 2,5-di(tert-butyl)-1,4-hydroquinone (10 μm), which causes depletion of the SR Ca2+, reduced the amplitude of the Ca2+ transient to 34 ± 1% of control, irrespective of the voltage.Brief exposure to extracellular Ca2+-free solution abolished the Ca2+ transients caused by depolarization while the caffeine-induced Ca2+ release persisted.Tetrodotoxin (1 μm) had no effect on the amplitude of the depolarization-induced Ca2+ transient, although it reduced the fast component of the inward current. In contrast, Ni2+ (5 mm) abolished the Ca2+ transients at any given voltage. Ni2+ also abolished spontaneous Ca2+ transients.In conclusion, in toad pacemaker cells Ca2+ release from SR contributes approximately 66% of the Ca2+ involved in the Ca2+ transient and requires extracellular Ca2+ influx to trigger its release. The L-type Ca2+ channels and Na+-Ca2+ exchange are major sources of Ca2+ influx under physiological conditions