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

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

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

Proactive Scalability and Management of Resources in Hybrid Clouds via Machine Learning

In this paper, we present a novel framework for supporting the management and optimization of application subject to software anomalies and deployed on large scale cloud architectures, composed of different geographically distributed cloud regions. The framework uses machine learning models for predicting failures caused by accumulation of anomalies. It introduces a novel workload balancing approach and a proactive system scale up/scale down technique. We developed a prototype of the framework and present some experiments for validating the applicability of the proposed approache

Prediction of human targets for viral-encoded microRNAs by thermodynamics and empirical constraints

MicroRNAs (miRNAs) are small RNA molecules that modulate gene expression through degradation of specific mRNAs and/or repression of their translation. miRNAs are involved in both physiological and pathological processes, such as apoptosis and cancer. Their presence has been demonstrated in several organisms as well as in viruses. Virus encoded miRNAs can act as viral gene expression regulators, but they may also interfere with the expression of host genes. Viral miRNAs may control host cell proliferation by targeting cell-cycle and apoptosis regulators. Therefore, they could be involved in cancer pathogenesis. Computational prediction of miRNA/target pairs is a fundamental step in these studies. Here, we describe the use of miRiam, a novel program based on both thermodynamics features and empirical constraints, to predict viral miRNAs/human targets interactions. miRiam exploits target mRNA secondary structure accessibility and interaction rules, inferred from validated miRNA/mRNA pairs. A set of genes involved in apoptosis and cell-cycle regulation was identified as target for our studies. This choice was supported by the knowledge that DNA tumor viruses interfere with the above processes in humans. miRNAs were selected from two cancer-related viruses, Epstein-Barr Virus (EBV) and Kaposi-Sarcoma-Associated Herpes Virus (KSHV). Results show that several transcripts possess potential binding sites for these miRNAs. This work has produced a set of plausible hypotheses of involvement of v-miRNAs and human apoptosis genes in cancer development. Our results suggest that during viral infection, besides the protein-based host regulation mechanism, a post-transcriptional level interference may exist. miRiam is freely available for downloading at http://ferrolab.dmi.unict.it/miriam