Tomography of core-mantle boundary and lowermost mantle coupled by geodynamics

We propose an innovative approach to mapping CMB topography from seismic P-wave traveltime inversions: instead of treating mantle velocity and CMB topography as independent parameters, as has been done so far, we account for their coupling by mantle flow, as formulated by Forte & Peltier. This approach rests on the assumption that P data are sufficiently sensitive to thermal heterogeneity, and that compositional heterogeneity, albeit important in localized regions of the mantle (e.g. within the D″ region), is not sufficiently strong to govern the pattern of mantle-wide convection and hence the CMB topography. The resulting tomographic maps of CMB topography are physically sound, and they resolve the known discrepancy between images obtained from classic tomography on the basis of core-reflected and core-refracted seismic phases. Since the coefficients of mantle velocity structure are the only free parameters of the inversion, this joint tomography-geodynamics approach reduces the number of parameters; nevertheless the corresponding mantle models fit the seismic data as well as the purely seismic one

EMT/MET at the crossroad of stemness, regeneration and oncogenesis. The Ying-Yang equilibrium recapitulated in cell spheroids

The epithelial-to-mesenchymal transition (EMT) is an essential trans-differentiation process, which plays a critical role in embryonic development, wound healing, tissue regeneration, organ fibrosis, and cancer progression. It is the fundamental mechanism by which epithelial cells lose many of their characteristics while acquiring features typical of mesenchymal cells, such as migratory capacity and invasiveness. Depending on the contest, EMT is complemented and balanced by the reverse process, the mesenchymal-to-epithelial transition (MET). In the saving economy of the living organisms, the same (Ying-Yang) tool is integrated as a physiological strategy in embryonic development, as well as in the course of reparative or disease processes, prominently fibrosis, tumor invasion and metastasis. These mechanisms and their related signaling (e.g., TGF-β and BMPs) have been effectively studied in vitro by tissue-derived cell spheroids models. These three-dimensional (3D) cell culture systems, whose phenotype has been shown to be strongly dependent on TGF-β-regulated EMT/MET processes, present the advantage of recapitulating in vitro the hypoxic in vivo micro-environment of tissue stem cell niches and their formation. These spheroids, therefore, nicely reproduce the finely regulated Ying-Yang equilibrium, which, together with other mechanisms, can be determinant in cell fate decisions in many pathophysiological scenarios, such as differentiation, fibrosis, regeneration, and oncogenesis. In this review, current progress in the knowledge of signaling pathways affecting EMT/MET and stemness regulation will be outlined by comparing data obtained from cellular spheroids systems, as ex vivo niches of stem cells derived from normal and tumoral tissues. The mechanistic correspondence in vivo and the possible pharmacological perspective will be also explored, focusing especially on the TGF-β-related networks, as well as others, such as SNAI1, PTEN, and EGR1. This latter, in particular, for its ability to convey multiple types of stimuli into relevant changes of the cell transcriptional program, can be regarded as a heterogeneous "stress-sensor" for EMT-related inducers (growth factor, hypoxia, mechano-stress), and thus as a therapeutic target

Nitric oxide, cytochrome c oxidase and myoglobin: Competition and reaction pathways

AbstractIt is relevant to cell physiology that nitric oxide (NO) reacts with both cytochrome oxidase (CcOX) and oxygenated myoglobin (MbO2). In this respect, it has been proposed [Pearce, L.L., et al. (2002) J. Biol. Chem. 277, 13556–13562] that (i) CcOX in turnover out-competes MbO2 for NO, and (ii) NO bound to reduced CcOX is “metabolized” in the active site to nitrite by reacting with O2. In contrast, rapid kinetics experiments reported in this study show that (i) upon mixing NO with MbO2 and CcOX in turnover, MbO2 out-competes the oxidase for NO and (ii) after mixing nitrosylated CcOX with O2 in the presence of MbO2, NO (and not nitrite) dissociates from the enzyme causing myoglobin oxidation

On the positivity of MSbar parton distributions

We revisit our argument that shows that parton distribution Functions (PDFs) in the MSbar{ scheme are non-negative in the perturbative region, with the main goals of elucidating its domain of validity and clarifying its theoretical underpinnings. We specifically discuss recent results proving that PDFs can turn negative at sufficiently low scale, we clarify quantitatively various aspects of our derivation of positivity in the perturbative region, and we provide an estimate for the scale above which PDF positivity holds

Nitrosative stress defences of the enterohepatic pathogenic bacterium Helicobacter pullorum

Helicobacter pullorum is an avian bacterium that causes gastroenteritis, intestinal bowel and hepatobiliary diseases in humans. Although H. pullorum has been shown to activate the mammalian innate immunity with release of nitric oxide (NO), the proteins that afford protection against NO and reactive nitrogen species (RNS) remain unknown. Here several protein candidates of H. pullorum, namely a truncated (TrHb) and a single domain haemoglobin (SdHb), and three peroxiredoxin-like proteins (Prx1, Prx2 and Prx3) were investigated. We report that the two haemoglobin genes are induced by RNS, and that SdHb confers resistance to nitrosative stress both in vitro and in macrophages. For peroxiredoxins, the prx2 and prx3 expression is enhanced by peroxynitrite and hydrogen peroxide, respectively. Mutation of prx1 does not alter the resistance to these stresses, while the single ∆prx2 and double ∆prx1∆prx2 mutants have decreased viability. To corroborate the physiological data, the biochemical analysis of the five recombinant enzymes was done, namely by stopped-flow spectrophotometry. It is shown that H. pullorum SdHb reacts with NO much more quickly than TrHb, and that the three Prxs react promptly with peroxynitrite, Prx3 displaying the highest reactivity. Altogether, the results unveil SdHb and Prx3 as major protective systems of H. pullorum against nitrosative stress

Insight Into Parkinson\u27s Disease Using Yeast as a Model to Evaluate the Role of Autophagy Genes in alpha-Synuclein Toxicity

Parkinson’s disease is a fatal and incurable human neurodegenerative disorder that destroys midbrain neurons. The misfolding, accumulation, and aggregation of the protein alpha-synuclein is thought to kill these cells. Enhancing alpha-synuclein degradation may help prevent its accumulation and aggregation, while protecting cells against toxicity. For this thesis, we used the model organism budding yeast to evaluate the hypothesis that alpha-synuclein is degraded by the cellular organelle lysosome via a specific route: the MVB/endocytosis pathway. Specifically, we evaluated whether three disease-related properties of alpha-synuclein (aggregation, accumulation, and toxicity) worsened in yeast strains that were individually deleted for genes coding for proteins required for the MVB/endocytosis pathway. In support of our hypothesis, each gene deletion altered one or more alpha-synuclein properties. While our data indicates that the MVB pathway is a route for alpha-synuclein degradation, the specificity and extent of alpha-synuclein involvement with proteins within the ESCRT complexes appears unexpectedly complex

N-acetylcysteine serves as substrate of 3-mercaptopyruvate sulfurtransferase and stimulates sulfide metabolism in colon cancer cells

Hydrogen sulfide (H2S) is an endogenously produced signaling molecule. The enzymes 3-mercaptopyruvate sulfurtransferase (MST), partly localized in mitochondria, and the inner mitochondrial membrane-associated sulfide:quinone oxidoreductase (SQR), besides being respectively involved in the synthesis and catabolism of H2S, generate sulfane sulfur species such as persulfides and polysulfides, currently recognized as mediating some of the H2S biological effects. Reprogramming of H2S metabolism was reported to support cellular proliferation and energy metabolism in cancer cells. As oxidative stress is a cancer hallmark and N-acetylcysteine (NAC) was recently suggested to act as an antioxidant by increasing intracellular levels of sulfane sulfur species, here we evaluated the effect of prolonged exposure to NAC on the H2S metabolism of SW480 colon cancer cells. Cells exposed to NAC for 24 h displayed increased expression and activity of MST and SQR. Furthermore, NAC was shown to: (i) persist at detectable levels inside the cells exposed to the drug for up to 24 h and (ii) sustain H2S synthesis by human MST more effectively than cysteine, as shown working on the isolated recombinant enzyme. We conclude that prolonged exposure of colon cancer cells to NAC stimulates H2S metabolism and that NAC can serve as a substrate for human MST

New perspectives to repair a broken heart

The aim of cardiac cell therapy is to restore at least in part the functionality of the diseased or injured myocardium by the use of stem/ progenitor cells. Recent clinical trials have shown the safety of cardiac cell therapy and encouraging efficacy results. A surprisingly wide range of non-myogenic cell types improves ventricular function, suggesting that benefits may result in part from mechanisms that are distinct from true myocardial regeneration. While clinical trials explore cells derived from skeletal muscle and bone marrow, basic researchers are investigating sources of new cardiomyogenic cells, such as resident myocardial progenitors and embryonic stem cells. In this commentary we briefly review the evolution of cell-based cardiac repair, some progress that has been made toward this goal, and future perspectives in the regeneration of cardiac tissue. © 2009 Bentham Science Publishers Ltd

Cytochrome bd oxidase and nitric oxide: from reaction mechanisms to bacterial physiology.

International audience; Experimental evidence suggests that the prokaryotic respiratory cytochrome bd quinol oxidase is responsible for both bioenergetic functions and bacterial adaptation to different stress conditions. The enzyme, phylogenetically unrelated to the extensively studied heme-copper terminal oxidases, is found in many commensal and pathogenic bacteria. Here, we review current knowledge on the catalytic intermediates of cytochrome bd and their reactivity towards nitric oxide (NO). Available information is discussed in the light of the hypothesis that, owing to its high NO dissociation rate, cytochrome bd confers resistance to NO-stress, thereby providing a strategy for bacterial pathogens to evade the NO-mediated host immune attack