Molecular dynamics simulations of iron- and aluminum-loaded serum transferrin: Protonation of tyr188 is necessary to prompt metal release

Serum transferrin (sTf) carries iron in blood serum and delivers it into cells by receptor-mediated endocytosis. The protein can also bind other metals, including aluminum. The crystal structures of the metal-free and metal-loaded protein indicate that the metal release process involves an opening of the protein. In this process, Lys206 and Lys296 lying in the proximity of each other form the dilysine pair or, so-called, dilysine trigger. It was suggested that the conformational change takes place due to variations of the protonation state of the dilysine trigger at the acidic endosomal pH. In 2003, Rinaldo and Field (Biophys. J. 85, 3485-3501) proposed that the dilysine trigger alone can not explain the opening and that the protonation of Tyr188 is required to prompt the conformational change. However, no evidence was supplied to support this hypothesis. Here, we present several 60 ns molecular dynamics simulations considering various protonation states to investigate the complexes formed by sTf with Fe(III) and Al(III). The calculations demonstrate that only in those systems where Tyr188 has been protonated does the protein undergo the conformational change and that the dilysine trigger alone does not lead to the opening. The simulations also indicate that the metal release process is a stepwise mechanism, where the hinge-bending motion is followed by the hinge-twisting step. Therefore, the study demonstrates for the first time that the protonation of Tyr188 is required for the release of metal from the metal loaded sTf and provides valuable information about the whole process

Chitosan Induces Plant Hormones and Defenses in Tomato Root Exudates

In this work, we use electrophysiological and metabolomic tools to determine the role of chitosan as plant defense elicitor in soil for preventing or manage root pests and diseases sustainably. Root exudates include a wide variety of molecules that plants and root microbiota use to communicate in the rhizosphere. Tomato plants were treated with chitosan. Root exudates from tomato plants were analyzed at 3, 10, 20, and 30 days after planting (dap). We found, using high performance liquid chromatography (HPLC) and excitation emission matrix (EEM) fluorescence, that chitosan induces plant hormones, lipid signaling and defense compounds in tomato root exudates, including phenolics. High doses of chitosan induce membrane depolarization and affect membrane integrity. 1H-NMR showed the dynamic of exudation, detecting the largest number of signals in 20 dap root exudates. Root exudates from plants irrigated with chitosan inhibit ca. twofold growth kinetics of the tomato root parasitic fungus Fusarium oxysporum f. sp. radicis-lycopersici. and reduced ca. 1.5-fold egg hatching of the root-knot nematode Meloidogyne javanica.This work was supported by AGL 2015 66833-R Grant from the Spanish Ministry of Economy and Competitiveness and H2020 MUSA 727624 European Project

Giant pulmonary artery aneurysm in a patient with vasoreactive pulmonary hypertension: a case report

<p>Abstract</p> <p>Background</p> <p>Pulmonary artery aneurysms are a rare condition, frequently associated with pulmonary hypertension. However, the evolution and treatment of this pathology is still not clear.</p> <p>Case Presentation</p> <p>The authors report a case of a 65-year old patient with pulmonary artery aneurysm associated with pulmonary arterial hypertension. Due to a positive vasoreactivity test, treatment with calcium channel blockers was started with near normalization of the right cardiac pressures. Nevertheless, after 20 months of treatment, the pulmonary artery aneurysm size remained unchanged with an associated severe pulmonary regurgitation and causing extrinsic compression of the main left coronary artery. Surgical correction was successfully performed.</p> <p>Conclusions</p> <p>This is the first case report of a pulmonary artery aneurysm described to be associated with vasoreactive pulmonary hypertension in a living patient. Although medical therapy for pulmonary hypertension was started, surgical correction of the aneurysm was executed in order to prevent its future complications.</p

Top-Charm Associated Production in High Energy e+e−e^+e^- Collisions

The possibility of exploring the flavor changing neutral current $tcZ/tc\gamma$ couplings in the production vertex for the reaction \epem\to t\bar c + \bar tc is examined. Using a model independent parameterization for the effective Lagrangian to describe the most general three-point interactions, production cross sections are found to be relatively small at LEP II, but potentially sizeable at higher energy \epem colliders. The kinematic characteristics of the signal are studied and a set of cuts are devised for clean separation of the signal from background. The resulting sensitivity to anomalous flavor changing couplings at LEP II with an integrated luminosity of $4\times 500$ pb$^{-1}$ is found to be comparable to their present indirect constraints from loop processes, while at higher energy colliders with $0.5-1$ TeV center-of-mass energy and 50-200 fb$^{-1}$ luminosity, one expects to reach a sensitivity at or below the percentage level.Comment: Latex, 22 page

Tri-meson-mixing of π\pi-η\eta-η′\eta' and ρ\rho-ω\omega-ϕ\phi in the light-cone quark model

The radiative transition form factors of the pseudoscalar mesons {$\pi$, $\eta$, $\eta'$} and the vector mesons {$\rho$, $\omega$, $\phi$} are restudied with $\pi$-$\eta$-$\eta'$ and $\rho$-$\omega$-$\phi$ in tri-meson-mixing pattern, which is described by tri-mixing matrices in the light-cone constituent quark model. The experimental transition decay widths are better reproduced with tri-meson-mixing than previous results in a two-mixing-angle scenario of only two-meson $\eta$-$\eta'$ mixing and $\omega$-$\phi$ mixing.Comment: 8 pages, 6 figures, final version to appear in EPJ

The Muon Anomalous Magnetic Moment: A Harbinger For "New Physics"

QED, Hadronic, and Electroweak Standard Model contributions to the muon anomalous magnetic moment, a_mu = (g_mu-2)/2, and their theoretical uncertainties are scrutinized. The status and implications of the recently reported 2.6 sigma experiment vs.theory deviation a_mu^{exp}-a_mu^{SM} = 426(165) times 10^{-11} are discussed. Possible explanations due to supersymmetric loop effects with m_{SUSY} \simeq 55 sqrt{tan beta} GeV, radiative mass mechanisms at the 1--2 TeV scale and other ``New Physics'' scenarios are examined.Comment: 24 page

Probing Supergravity Grand Unification in the Brookhaven g-2 Experiment

A quantitative analysis of \amu\equiv{1\over 2}(g-2)_\mu within the framework of Supergravity Grand Unification and radiative breaking of the electro-weak symmetry is given. It is found that $a_{\mu}^{SUSY}$ is dominated by the chiral interference term from the light chargino exchange, and that this term carries a signature which correlates strongly with the sign of $\mu$. Thus as a rule $a_{\mu}^{SUSY}>0$ for $\mu>0$ and $a_{\mu}^{SUSY}<0$ for $\mu<0$ with very few exceptions when tan$\beta\sim 1$. At the quantitative level it is shown that if the E821 BNL experiment can reach the expected sensitivity of $4\times 10^{-10}$ and there is a reduction in the hadronic error by a factor of four or more, then the experiment will explore a majority of the parameter space in $m_0-m_{\tilde g}$ plane in the region m_0\lsim 400 GeV, m_{\tilde g}\lsim 700 GeV for \tanbeta \gsim 10 assuming the experiment will not discard the Standard Model result within its $2\sigma$ uncertainty limit. For smaller \tanbeta, the SUSY reach of E821 will still be considerable. Further, if no effect within $2 \sigma$ limit of the Standard Model value is seen, then large \tanbeta scenarios will be severely constrained within the current naturalness criterion, ie., m_0, m_{\tilde g}\lsim 1 TeV.Comment: 27 pages, Latex, uuencoded figure file to be obtained and processed separately for two figures. Figures may also be sent on request by mai

Influence of IL28B Polymorphisms on Response to a Lower-Than-Standard Dose peg-IFN-α 2a for Genotype 3 Chronic Hepatitis C in HIV-Coinfected Patients

Background: Data on which to base definitive recommendations on the doses and duration of therapy for genotype 3 HCV/HIV-coinfected patients are scarce. We evaluated the efficacy of a lower peginterferon-α 2a dose and a shorter duration of therapy than the current standard of care in genotype 3 HCV/HIV-coinfected patients. Methods and Findings: Pilot, open-label, single arm clinical trial which involved 58 Caucasian HCV/HIV-coinfected patients who received weekly 135 μg peginterferon-α 2a plus ribavirin 400 mg twice daily during 20 weeks after attaining undetectable viremia. The relationships between baseline patient-related variables, including IL28B genotype, plasma HCV-RNA, ribavirin dose/kg, peginterferon-α 2a and ribavirin levels with virological responses were analyzed. Only 4 patients showed lack of response and 5 patients dropped out due to adverse events related to the study medication. Overall, sustained virologic response (SVR) rates were 58.3% by intention-to-treat and 71.4% by per protocol analysis, respectively. Among patients with rapid virologic response (RVR), SVR and relapses rates were 92.6% and 7.4%, respectively. No relationships were observed between viral responses and ribavirin dose/kg, peginterferon-α 2a concentrations, ribavirin levels or rs129679860 genotype. Conclusions: Weekly 135 μg pegIFN-α 2a could be as effective as the standard 180 μg dose, with a very low incidence of severe adverse events. A 24-week treatment duration appears to be appropriate in patients achieving RVR, but extending treatment up to just 20 weeks beyond negativization of viremia is associated with a high relapse rate in those patients not achieving RVR. There was no influence of IL28B genotype on the virological responses. © 2012 López-Cortés et al.Funding provided by Fundación Pública Andaluza para la gestión de la Investigación en Salud de Sevilla. Hospitales Universitarios Virgen del Rocío. Seville, Spain. The enzyme-linked immunosorbent assay Hu-INF-α kits for determination of pegIFN-α-2a were financed by Roche Pharma, S.A. (Spain).Peer Reviewe

Rate and duration of hospitalisation for acute pulmonary embolism in the real-world clinical practice of different countries : Analysis from the RIETE registry

publishersversionPeer reviewe

Self-Reactivities to the Non-Erythroid Alpha Spectrin Correlate with Cerebral Malaria in Gabonese Children

BACKGROUND: Hypergammaglobulinemia and polyclonal B-cell activation commonly occur in Plasmodium sp. infections. Some of the antibodies produced recognize self-components and are correlated with disease severity in P. falciparum malaria. However, it is not known whether some self-reactive antibodies produced during P. falciparum infection contribute to the events leading to cerebral malaria (CM). We show here a correlation between self-antibody responses to a human brain protein and high levels of circulating TNF alpha (TNFα), with the manifestation of CM in Gabonese children. METHODOLOGY: To study the role of self-reactive antibodies associated to the development of P. falciparum cerebral malaria, we used a combination of quantitative immunoblotting and multivariate analysis to analyse correlation between the reactivity of circulating IgG with a human brain protein extract and TNFα concentrations in cohorts of uninfected controls (UI) and P. falciparum-infected Gabonese children developing uncomplicated malaria (UM), severe non-cerebral malaria (SNCM), or CM. RESULTS/CONCLUSION: The repertoire of brain antigens recognized by plasma IgGs was more diverse in infected than in UI individuals. Anti-brain reactivity was significantly higher in the CM group than in the UM and SNCM groups. IgG self-reactivity to brain antigens was also correlated with plasma IgG levels and age. We found that 90% of CM patients displayed reactivity to a high-molecular mass band containing the spectrin non-erythroid alpha chain. Reactivity with this band was correlated with high TNFα concentrations in CM patients. These results strongly suggest that an antibody response to brain antigens induced by P. falciparum infection may be associated with pathogenic mechanisms in patients developing CM