Magnetoelectric effect due to local noncentrosymmetry

Magnetoelectrics often possess ions located in noncentrosymmetric surroundings. Based on this fact we suggest a microscopic model of magnetoelectric interaction and show that the spin-orbit coupling leads to spin-dependent electric dipole moments of the electron orbitals of these ions, which results in non-vanishing polarization for certain spin configurations. The approach accounts for the macroscopic symmetry of the unit cell and is valid both for commensurate and complex incommensurate magnetic structures. The model is illustrated by the examples of MnWO4, MnPS3 and LiNiPO4. Application to other magnetoelectrics is discussed.Comment: 11 pages, 2 figures, 2 table

Effects of antenatal betamethasone on preterm human and mouse ductus arteriosus: comparison with baboon data.

BackgroundAlthough studies involving preterm infants ≤34 weeks gestation report a decreased incidence of patent ductus arteriosus after antenatal betamethasone, studies involving younger gestation infants report conflicting results.MethodsWe used preterm baboons, mice, and humans (≤276/7 weeks gestation) to examine betamethasone's effects on ductus gene expression and constriction both in vitro and in vivo.ResultsIn mice, betamethasone increased the sensitivity of the premature ductus to the contractile effects of oxygen without altering the effects of other contractile or vasodilatory stimuli. Betamethasone's effects on oxygen sensitivity could be eliminated by inhibiting endogenous prostaglandin/nitric oxide signaling. In mice and baboons, betamethasone increased the expression of several developmentally regulated genes that mediate oxygen-induced constriction (K+ channels) and inhibit vasodilator signaling (phosphodiesterases). In human infants, betamethasone increased the rate of ductus constriction at all gestational ages. However, in infants born ≤256/7 weeks gestation, betamethasone's contractile effects were only apparent when prostaglandin signaling was inhibited, whereas at 26-27 weeks gestation, betamethasone's contractile effects were apparent even in the absence of prostaglandin inhibitors.ConclusionsWe speculate that betamethasone's contractile effects may be mediated through genes that are developmentally regulated. This could explain why betamethasone's effects vary according to the infant's developmental age at birth

The dynamic relationships between the three events that release individual Na+ ions from the Na+/K+-ATPase

© Macmillan Publishers Limited, 2012. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Nature Communications 3 (2012): 669, doi:10.1038/ncomms1673.Na+/K+ pumps move net charge through the cell membrane by mediating unequal exchange of intracellular Na+ and extracellular K+. Most charge moves during transitions that release Na+ to the cell exterior. When pumps are constrained to bind and release only Na+, a membrane voltage-step redistributes pumps among conformations with zero, one, two or three bound Na+, thereby transiently generating current. By applying rapid voltage steps to squid giant axons, we previously identified three components in such transient currents, with distinct relaxation speeds: fast (which nearly parallels the voltage-jump time course), medium speed (τm=0.2–0.5 ms) and slow (τs=1–10 ms). Here we show that these three components are tightly correlated, both in their magnitudes and in the time courses of their changes. The correlations reveal the dynamics of the conformational rearrangements that release three Na+ to the exterior (or sequester them into their binding sites) one at a time, in an obligatorily sequential manner.This research was directly supported by the Intramural Research Program of the National Institutes of Health (NIH), NINDS, grants NIH HL36783 to D.C.G., and NIH U54GM087519 and R01GM030376 to F.B

Atomic-Level Characterization of the Activation Mechanism of SERCA by Calcium

We have performed molecular dynamics (MD) simulations to elucidate, in atomic detail, the mechanism by which the sarcoplasmic reticulum Ca2+-ATPase (SERCA) is activated by Ca2+. Crystal structures suggest that activation of SERCA occurs when the cytoplasmic head-piece, in an open (E1) conformation stabilized by Ca2+, undergoes a large-scale open-to-closed (E1 to E2) transition that is induced by ATP binding. However, spectroscopic measurements in solution suggest that these structural states (E1 and E2) are not tightly coupled to biochemical states (defined by bound ligands); the closed E2 state predominates even in the absence of ATP, in both the presence and absence of Ca2+. How is this loose coupling consistent with the high efficiency of energy transduction in the Ca2+-ATPase? To provide insight into this question, we performed long (500 ns) all-atom MD simulations starting from the open crystal structure, including a lipid bilayer and water. In both the presence and absence of Ca2+, we observed a large-scale open-to-closed conformational transition within 400 ns, supporting the weak coupling between structural and biochemical states. However, upon closer inspection, it is clear that Ca2+ is necessary and sufficient for SERCA to reach the precise geometrical arrangement necessary for activation of ATP hydrolysis. Contrary to suggestions from crystal structures, but in agreement with solution spectroscopy, the presence of ATP is not required for this activating transition. Principal component analysis showed that Ca2+ reshapes the free energy landscape of SERCA to create a path between the open conformation and the activated closed conformation. Thus the malleability of the free energy landscape is essential for SERCA efficiency, ensuring that ATP hydrolysis is tightly coupled to Ca2+ transport. These results demonstrate the importance of real-time dynamics in the formation of catalytically competent conformations of SERCA, with broad implications for understanding enzymatic catalysis in atomic detail

Control of Gastric H,K-ATPase Activity by Cations, Voltage and Intracellular pH Analyzed by Voltage Clamp Fluorometry in Xenopus Oocytes

Whereas electrogenic partial reactions of the Na,K-ATPase have been studied in depth, much less is known about the influence of the membrane potential on the electroneutrally operating gastric H,K-ATPase. In this work, we investigated site-specifically fluorescence-labeled H,K-ATPase expressed in Xenopus oocytes by voltage clamp fluorometry to monitor the voltage-dependent distribution between E1P and E2P states and measured Rb+ uptake under various ionic and pH conditions. The steady-state E1P/E2P distribution, as indicated by the voltage-dependent fluorescence amplitudes and the Rb+ uptake activity were highly sensitive to small changes in intracellular pH, whereas even large extracellular pH changes affected neither the E1P/E2P distribution nor transport activity. Notably, intracellular acidification by approximately 0.5 pH units shifted V0.5, the voltage, at which the E1P/E2P ratio is 50∶50, by −100 mV. This was paralleled by an approximately two-fold acceleration of the forward rate constant of the E1P→E2P transition and a similar increase in the rate of steady-state cation transport. The temperature dependence of Rb+ uptake yielded an activation energy of ∼90 kJ/mol, suggesting that ion transport is rate-limited by a major conformational transition. The pronounced sensitivity towards intracellular pH suggests that proton uptake from the cytoplasmic side controls the level of phosphoenzyme entering the E1P→E2P conformational transition, thus limiting ion transport of the gastric H,K-ATPase. These findings highlight the significance of cellular mechanisms contributing to increased proton availability in the cytoplasm of gastric parietal cells. Furthermore, we show that extracellular Na+ profoundly alters the voltage-dependent E1P/E2P distribution indicating that Na+ ions can act as surrogates for protons regarding the E2P→E1P transition. The complexity of the intra- and extracellular cation effects can be rationalized by a kinetic model suggesting that cations reach the binding sites through a rather high-field intra- and a rather low-field extracellular access channel, with fractional electrical distances of ∼0.5 and ∼0.2, respectively

Identification of the Rem-responsive element of mouse mammary tumor virus

Mouse mammary tumor virus (MMTV) has previously been shown to encode a functional homolog of the human immunodeficiency virus-1 (HIV-1) nuclear export protein Rev, termed Rem. Here, we show that deletion of the rem gene from a MMTV molecular clone interfered with the nucleo-cytoplasmic transport of genomic length viral mRNA and resulted in a loss of viral capsid (Gag) protein production. Interestingly, nuclear export of single-spliced env mRNA was only moderately affected, suggesting that this transcript is, at least to some extent, transported via a distinct, Rem-independent export mechanism. To identify and characterize a cis-acting RNA element required for Rem responsiveness (RmRE), extensive computational and functional analyses were performed. By these means a region of 490 nt corresponding to positions nt 8517–nt 9006 in the MMTV reference strain was identified as RmRE. Deletion of this fragment, which spans the env-U3 junction region, abolished Gag expression. Furthermore, insertion of this sequence into a heterologous HIV-1-based reporter construct restored, in the presence of Rem, HIV-1 Gag expression to levels determined for the Rev/RRE export system. These results clearly demonstrate that the identified region, whose geometry resembles that of other retroviral-responsive elements, is capable to functionally substitute, in the presence of Rem, for Rev/RRE and thus provide unequivocal evidence that MMTV is a complex retrovirus

Exploring the Conformational Transitions of Biomolecular Systems Using a Simple Two-State Anisotropic Network Model

Biomolecular conformational transitions are essential to biological functions. Most experimental methods report on the long-lived functional states of biomolecules, but information about the transition pathways between these stable states is generally scarce. Such transitions involve short-lived conformational states that are difficult to detect experimentally. For this reason, computational methods are needed to produce plausible hypothetical transition pathways that can then be probed experimentally. Here we propose a simple and computationally efficient method, called ANMPathway, for constructing a physically reasonable pathway between two endpoints of a conformational transition. We adopt a coarse-grained representation of the protein and construct a two-state potential by combining two elastic network models (ENMs) representative of the experimental structures resolved for the endpoints. The two-state potential has a cusp hypersurface in the configuration space where the energies from both the ENMs are equal. We first search for the minimum energy structure on the cusp hypersurface and then treat it as the transition state. The continuous pathway is subsequently constructed by following the steepest descent energy minimization trajectories starting from the transition state on each side of the cusp hypersurface. Application to several systems of broad biological interest such as adenylate kinase, ATP-driven calcium pump SERCA, leucine transporter and glutamate transporter shows that ANMPathway yields results in good agreement with those from other similar methods and with data obtained from all-atom molecular dynamics simulations, in support of the utility of this simple and efficient approach. Notably the method provides experimentally testable predictions, including the formation of non-native contacts during the transition which we were able to detect in two of the systems we studied. An open-access web server has been created to deliver ANMPathway results. © 2014 Das et al

Elucidation of the ATP7B N-Domain Mg2+-ATP Coordination Site and Its Allosteric Regulation

The diagnostic of orphan genetic disease is often a puzzling task as less attention is paid to the elucidation of the pathophysiology of these rare disorders at the molecular level. We present here a multidisciplinary approach using molecular modeling tools and surface plasmonic resonance to study the function of the ATP7B protein, which is impaired in the Wilson disease. Experimentally validated in silico models allow the elucidation in the Nucleotide binding domain (N-domain) of the Mg2+-ATP coordination site and answer to the controversial role of the Mg2+ ion in the nucleotide binding process. The analysis of protein motions revealed a substantial effect on a long flexible loop branched to the N-domain protein core. We demonstrated the capacity of the loop to disrupt the interaction between Mg2+-ATP complex and the N-domain and propose a role for this loop in the allosteric regulation of the nucleotide binding process

Rapid Detection of Infestation of Apple Fruits by the Peach Fruit Moth, Carposina sasakii Matsumura, Larvae Using a 0.2-T Dedicated Magnetic Resonance Imaging Apparatus

Infestation of harvested apple fruits by the peach fruit moth (Carposina sasakii Matsumura) was studied using a dedicated magnetic resonance imaging (MRI) apparatus equipped with a 0.2-T permanent magnet. Infested holes on the three-dimensional (3-D) images tracked ecological movements of peach fruit moth larvae within the food fruits, and thus in their natural habitat. Sensitive short solenoid coil and surface coil detectors were devised to shorten measurement times. The short solenoid coil detected infestation holes at a rate of 6.4 s per image by the single-slice 2-D measurement. The multi-slice 2-D measurement provided six slice images of a fruit within 2 min taken by the two detectors. These results indicate that the 0.2-T MRI apparatus allows one to distinguish sound fruits from infested ones, and also as a means for plant protection and the preservation of natural ecological systems in foreign trade