Mitochondrial peroxiredoxin functions as crucial chaperone reservoir in Leishmania infantum

Cytosolic eukaryotic 2-Cys-peroxiredoxins have been widely reported to act as dual-function proteins, either detoxifying reactive oxygen species or acting as chaperones to prevent protein aggregation. Several stimuli, including peroxide-mediated sulfinic acid formation at the active site cysteine, have been proposed to trigger the chaperone activity. However, the mechanism underlying this activation and the extent to which the chaperone function is crucial under physiological conditions in vivo remained unknown. Here we demonstrate that in the vector-borne protozoan parasite Leishmania infantum, mitochondrial peroxiredoxin (Prx) exerts intrinsic ATP-independent chaperone activity, protecting a wide variety of different proteins against heat stress-mediated unfolding in vitro and in vivo. Activation of the chaperone function appears to be induced by temperature-mediated restructuring of the reduced decamers, promoting binding of unfolding client proteins in the center of Prx's ringlike structure. Client proteins are maintained in a folding-competent conformation until restoration of nonstress conditions, upon which they are released and transferred to ATP-dependent chaperones for refolding. Interference with client binding impairs parasite infectivity, providing compelling evidence for the in vivo importance of Prx's chaperone function. Our results suggest that reduced Prx provides a mitochondrial chaperone reservoir, which allows L. infantum to deal successfully with protein unfolding conditions during the transition from insect to the mammalian hosts and to generate viable parasites capable of perpetuating infection.We thank Frederico Silva for help with size-exclusion chromatography experiments, and Ana G. Gomes-Alves and Ricardo Silva for constructing the pSSU-PHLEO-infantum-MTS.His.THR-mTXNPx plasmid. This work was supported by National Institutes of Health Grant GM065318 (to U.J.) and Project "NORTE-07-0124-FEDER-000002-Host-Pathogen Interactions" cofunded by Programa Operacional Regional do Norte under the Quadro de Referencia Estrategico Nacional, through Fundo Europeu de Desenvolvimento Regional, and by the Portuguese Foundation for Science and Technology (FCT) (A.M.T.). F.T. and H.C. were supported by Portuguese FCT Fellowships SFRH/BD/70438/2010 and SFRH/BPD/80836/2011, respectively

Crystal-like high frequency phonons in the amorphous phases of solid water

The high frequency dynamics of low- (LDA) and high-density amorphous-ice (HDA) and of cubic ice (I_c) has been measured by inelastic X-ray Scattering (IXS) in the 1-15 nm^{-1} momentum transfer (Q) range. Sharp phonon-like excitations are observed, and the longitudinal acoustic branch is identified up to Q = 8nm^{-1} in LDA and I_c and up to 5nm^{-1} in HDA. The narrow width of these excitations is in sharp contrast with the broad features observed in all amorphous systems studied so far. The "crystal-like" behavior of amorphous ices, therefore, implies a considerable reduction in the number of decay channels available to sound-like excitations which is assimilated to low local disorder.Comment: 4 pages, 3 figure

Safety of magnetic resonance imaging scanning in patients with cardiac resynchronization therapy–defibrillators incorporating quadripolar left ventricular leads

© 2020 The Authors Background: Magnetic resonance imaging (MRI) scanning of magnetic resonance (MR)-conditional cardiac implantable cardioverter-defibrillators (ICDs) can be performed safely following specific protocols. MRI safety with cardiac resynchronization therapy–defibrillators (CRT-Ds) incorporating quadripolar left ventricular (LV) leads is less clear. Objective: The purpose of this study was to evaluate the safety and effectiveness of ICDs and CRT-D systems with quadripolar LV leads after an MRI scan. Methods: The ENABLE MRI Study included 230 subjects implanted with a Boston Scientific ImageReady ICD (n = 39) or CRT-D (n = 191) incorporating quadripolar LV leads undergoing nondiagnostic 1.5-T MRI scans (lumbar and thoracic spine imaging) a minimum of 6 weeks postimplant. Pacing capture thresholds (PCTs), sensing amplitudes (SAs), and impedances were measured before and 1 month post-MRI using the same programmed LV pacing vectors. The ability to sense/treat ventricular fibrillation (VF) was assessed in a subset of patients. Results: A total of 159 patients completed a protocol-required MRI scan (MRI Protection Mode turned on) with no scan-related complications. All right ventricular (RV) and left LV PCT and SA effectiveness endpoints were met: RV PCT 99% (145/146 patients), LV PCT 100% (120/120), RV SA 99% (145/146), and LV SA 98% (116/118). In no instances did MRI result in a change in pacing vector or lead revision. All episodes of VF were appropriately sensed and treated. Conclusion: This first evaluation of predominantly CRT-D systems with quadripolar LV leads undergoing 1.5-T MRI confirmed that scanning was safe with no significant changes in RV/LV PCT, SA, programmed vectors, and VF treatment, thus suggesting that MRI in patients having a device with quadripolar leads can be performed without negative impact on CRT delivery

Effect of Chronic Escitalopram versus Placebo on Personality Traits in Healthy First-Degree Relatives of Patients with Depression: A Randomized Trial

The serotonergic neurotransmitter system is closely linked to depression and personality traits. It is not known if selective serotonin reuptake inhibitors (SSRI) have an effect on neuroticism that is independent of their effect on depression. Healthy individuals with a genetic liability for depression represent a group of particular interest when investigating if intervention with SSRIs affects personality. The present trial is the first to test the hypothesis that escitalopram may reduce neuroticism in healthy first-degree relatives of patients with major depressive disorder (MD).The trial used a randomized, blinded, placebo-controlled parallel-group design. We examined the effect of four weeks escitalopram 10 mg daily versus matching placebo on personality in 80 people who had a biological parent or sibling with a history of MD. The outcome measure on personality traits was change in self-reported neuroticism scores on the Revised Neuroticism-Extroversion-Openness-Personality Inventory (NEO-PI-R) and the Eysenck Personality Inventory (EPQ) from entry until end of four weeks of intervention.When compared with placebo, escitalopram did not significantly affect self-reported NEO-PI-R and EPQ neuroticism and extroversion, EPQ psychoticism, NEO-PI-R openness, or NEO-PI-R conscientiousness (p all above 0.05). However, escitalopram increased NEO-PI-R agreeableness scores significantly compared with placebo (mean; SD) (2.38; 8.09) versus (-1.32; 7.94), p = 0.046), but not following correction for multiplicity. A trend was shown for increased conscientiousness (p = 0.07). There was no significant effect on subclinical depressive symptoms (p = 0.6).In healthy first-degree relatives of patients with MD, there is no effect of escitalopram on neuroticism, but it is possible that escitalopram may increase the personality traits of agreeableness and conscientiousness.Clinicaltrials.gov NCT00386841

Pressure dependent electronic properties of MgO polymorphs: A first-principles study of Compton profiles and autocorrelation functions

The first-principles periodic linear combination of atomic orbitals method within the framework of density functional theory implemented in the CRYSTAL06 code has been applied to explore effect of pressure on the Compton profiles and autocorrelation functions of MgO. Calculations are performed for the B1, B2, B3, B4, B8_1 and h-MgO polymorphs of MgO to compute lattice constants and bulk moduli. The isothermal enthalpy calculations predict that B4 to B8_1, h-MgO to B8_1, B3 to B2, B4 to B2 and h-MgO to B2 transitions take place at 2, 9, 37, 42 and 64 GPa respectively. The high pressure transitions B8_1 to B2 and B1 to B2 are found to occur at 340 and 410 GPa respectively. The pressure dependent changes are observed largely in the valence electrons Compton profiles whereas core profiles are almost independent of the pressure in all MgO polymorphs. Increase in pressure results in broadening of the valence Compton profiles. The principal maxima in the second derivative of Compton profiles shifts towards high momentum side in all structures. Reorganization of momentum density in the B1 to B2 structural phase transition is seen in the first and second derivatives before and after the transition pressure. Features of the autocorrelation functions shift towards lower r side with increment in pressure.Comment: 19 pages, 8 figures, accepted for publication in Journal of Materials Scienc

Photoelasticity of crystalline and amorphous silica from first principles

Based on density-functional perturbation theory we have computed from first principles the photoelastic tensor of few crystalline phases of silica at normal conditions and high pressure (quartz, $\alpha$-cristobalite, $\beta$-cristobalite) and of models of amorphous silica (containig up to 162 atoms), obtained by quenching from the melt in combined classical and Car-Parrinello molecular dynamics simulations. The computational framework has also been checked on the photoelastic tensor of crystalline silicon and MgO as prototypes of covalent and ionic systems. The agreement with available experimental data is good. A phenomenological model suitable to describe the photoelastic properties of different silica polymorphs is devised by fitting on the ab-initio data.Comment: ten figure

A combined computational and experimental investigation of the [2Fe–2S] cluster in biotin synthase

Biotin synthase was the first example of what is now regarded as a distinctive enzyme class within the radical S-adenosylmethionine superfamily, the members of which use Fe/S clusters as the sulphur source in radical sulphur insertion reactions. The crystal structure showed that this enzyme contains a [2Fe–2S] cluster with a highly unusual arginine ligand, besides three normal cysteine ligands. However, the crystal structure is at such a low resolution that neither the exact coordination mode nor the role of this exceptional ligand has been elucidated yet, although it has been shown that it is not essential for enzyme activity. We have used quantum refinement of the crystal structure and combined quantum mechanical and molecular mechanical calculations to explore possible coordination modes and their influences on cluster properties. The investigations show that the protonation state of the arginine ligand has little influence on cluster geometry, so even a positively charged guanidinium moiety would be in close proximity to the iron atom. Nevertheless, the crystallised enzyme most probably contains a deprotonated (neutral) arginine coordinating via the NH group. Furthermore, the Fe···Fe distance seems to be independent of the coordination mode and is in perfect agreement with distances in other structurally characterised [2Fe–2S] clusters. The exceptionally large Fe···Fe distance found in the crystal structure could not be reproduced

Collaborative Broadcast in O(log log n) Rounds

We consider the multihop broadcasting problem for $n$ nodes placed uniformly at random in a disk and investigate the number of hops required to transmit a signal from the central node to all other nodes under three communication models: Unit-Disk-Graph (UDG), Signal-to-Noise-Ratio (SNR), and the wave superposition model of multiple input/multiple output (MIMO). In the MIMO model, informed nodes cooperate to produce a stronger superposed signal. We do not consider the problem of transmitting a full message nor do we consider interference. In each round, the informed senders try to deliver to other nodes the required signal strength such that the received signal can be distinguished from the noise. We assume sufficiently high node density $\rho= \Omega(\log n)$. In the unit-disk graph model, broadcasting needs $O(\sqrt{n/\rho})$ rounds. In the other models, we use an Expanding Disk Broadcasting Algorithm, where in a round only triggered nodes within a certain distance from the initiator node contribute to the broadcasting operation. This algorithm achieves a broadcast in only $O(\frac{\log n}{\log \rho})$ rounds in the SNR-model. Adapted to the MIMO model, it broadcasts within $O(\log \log n - \log \log \rho)$ rounds. All bounds are asymptotically tight and hold with high probability, i.e. $1- n^{-O(1)}$.Comment: extended abstract accepted for ALGOSENSORS 201

Pattern formation in 2-frequency forced parametric waves

We present an experimental investigation of superlattice patterns generated on the surface of a fluid via parametric forcing with 2 commensurate frequencies. The spatio-temporal behavior of 4 qualitatively different types of superlattice patterns is described in detail. These states are generated via a number of different 3--wave resonant interactions. They occur either as symmetry--breaking bifurcations of hexagonal patterns composed of a single unstable mode or via nonlinear interactions between the two primary unstable modes generated by the two forcing frequencies. A coherent picture of these states together with the phase space in which they appear is presented. In addition, we describe a number of new superlattice states generated by 4--wave interactions that arise when symmetry constraints rule out 3--wave resonances.Comment: The paper contains 34 pages and 53 figures and provides an extensive review of both the theoretical and experimental work peformed in this syste

Visual onset expands subjective time

We report a distortion of subjective time perception in which the duration of a first interval is perceived to be longer than the succeeding interval of the same duration. The amount of time expansion depends on the onset type defining the first interval. When a stimulus appears abruptly, its duration is perceived to be longer than when it appears following a stationary array. The difference in the processing time for the stimulus onset and motion onset, measured as reaction times, agrees with the difference in time expansion. Our results suggest that initial transient responses for a visual onset serve as a temporal marker for time estimation, and a systematic change in the processing time for onsets affects perceived time