Methylation potential associated with diet,genotype, protein,and metabolite levels in the Delta Obesity Vitamin Study

Micronutrient research typically focuses on analyzing the effects of single or a few nutrients on health by analyzing a limited number of biomarkers. The observational study described here analyzed micronutrients, plasma proteins, dietary intakes, and genotype using a systems approach. Participants attended a community-based summer day program for 6–14 year old in 2 years. Genetic makeup, blood metabolite and protein levels, and dietary differences were measured in each individual. Twenty-four-hour dietary intakes, eight micronutrients (vitamins A, D, E, thiamin, folic acid, riboflavin, pyridoxal, and pyridoxine) and 3 one-carbon metabolites [homocysteine (Hcy), S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH)], and 1,129 plasma proteins were analyzed as a function of diet at metabolite level, plasma protein level, age, and sex. Cluster analysis identified two groups differing in SAM/SAH and differing in dietary intake patterns indicating that SAM/SAH was a potential marker of nutritional status. The approach used to analyze genetic association with the SAM/SAH metabolites is called middle-out: SNPs in 275 genes involved in the one-carbon pathway (folate, pyridoxal/pyridoxine, thiamin) or were correlated with SAM/SAH (vitamin A, E, Hcy) were analyzed instead of the entire 1M SNP data set. This procedure identified 46 SNPs in 25 genes associated with SAM/SAH demonstrating a genetic contribution to the methylation potential. Individual plasma metabolites correlated with 99 plasma proteins. Fourteen proteins correlated with body mass index, 49 with group age, and 30 with sex. The analytical strategy described here identified subgroups for targeted nutritional interventions.

Electronic supplementary material

The online version of this article (doi:10.1007/s12263-014-0403-9) contains supplementary material, which is available to authorized users.     

Understanding Odor Information Segregation in the Olfactory Bulb by Means of Mitral and Tufted Cells

Odor identification is one of the main tasks of the olfactory system. It is performed almost independently from the concentration of the odor providing a robust recognition. This capacity to ignore concentration information does not preclude the olfactory system from estimating concentration itself. Significant experimental evidence has indicated that the olfactory system is able to infer simultaneously odor identity and intensity. However, it is still unclear at what level or levels of the olfactory pathway this segregation of information occurs. In this work, we study whether this odor information segregation is performed at the input stage of the olfactory bulb: the glomerular layer. To this end, we built a detailed neural model of the glomerular layer based on its known anatomical connections and conducted two simulated odor experiments. In the first experiment, the model was exposed to an odor stimulus dataset composed of six different odorants, each one dosed at six different concentrations. In the second experiment, we conducted an odor morphing experiment where a sequence of binary mixtures going from one odor to another through intermediate mixtures was presented to the model. The results of the experiments were visualized using principal components analysis and analyzed with hierarchical clustering to unveil the structure of the high-dimensional output space. Additionally, Fisher''s discriminant ratio and Pearson''s correlation coefficient were used to quantify odor identity and odor concentration information respectively. Our results showed that the architecture of the glomerular layer was able to mediate the segregation of odor information obtaining output spiking sequences of the principal neurons, namely the mitral and external tufted cells, strongly correlated with odor identity and concentration, respectively. An important conclusion is also that the morphological difference between the principal neurons is not key to achieve odor information segregation.     

Drug induced exfoliative dermatitis: state of the art

Drug induced exfoliative dermatitis (ED) are a group of rare and severe drug hypersensitivity reactions (DHR) involving skin and usually occurring from days to several weeks after drug exposure. Erythema multiforme (EM), Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are the main clinical presentations of drug induced ED. Overall, T cells are the central player of these immune-mediated drug reactions. Here we provide a systematic review on frequency, risk factors, pathogenesis, clinical features and management of patients with drug induced ED.     

Chronic myelogenous leukaemia exosomes modulate bone marrow microenvironment through activation of epidermal growth factor receptor

Chronic myelogenous leukaemia (CML) is a clonal myeloproliferative disorder. Recent evidence indicates that altered crosstalk between CML and mesenchymal stromal cells may affect leukaemia survival; moreover, vesicles released by both tumour and non‐tumour cells into the microenvironment provide a suitable niche for cancer cell growth and survival. We previously demonstrated that leukaemic and stromal cells establish an exosome‐mediated bidirectional crosstalk leading to the production of IL8 in stromal cells, thus sustaining the survival of CML cells. Human cell lines used are LAMA84 (CML cells), HS5 (stromal cells) and bone marrow primary stromal cells; gene expression and protein analysis were performed by real‐time PCR and Western blot. IL8 and MMP9 secretions were evaluated by ELISA. Exosomes were isolated from CML cells and blood samples of CML patients. Here, we show that LAMA84 and CML patients’ exosomes contain amphiregulin (AREG), thus activating epidermal growth factor receptor (EGFR) signalling in stromal cells. EGFR signalling increases the expression of SNAIL and its targets, MMP9 and IL8. We also demonstrated that pre‐treatment of HS5 with LAMA84 exosomes increases the expression of annexin A2 that promotes the adhesion of leukaemic cells to the stromal monolayer, finally supporting the growth and invasiveness of leukaemic cells. Leukaemic and stromal cells establish a bidirectional crosstalk: exosomes promote proliferation and survival of leukaemic cells, both in vitro and in vivo, by inducing IL8 secretion from stromal cells. We propose that this mechanism is activated by a ligand–receptor interaction between AREG, found in CML exosomes, and EGFR in bone marrow stromal cells.     

The Helicobacter pylori CagD (HP0545, Cag24) Protein Is Essential for CagA Translocation and Maximal Induction of Interleukin-8 Secretion

Pathogenic strains of Helicobacter pylori use a type IV secretion system (T4SS) to deliver the toxin CagA into human host cells. The T4SS, along with the toxin itself, is coded into a genomic insert, which is termed the cag pathogenicity island. The cag pathogenicity island contains about 30 open-reading frames, for most of which the exact function is not well characterized or totally unknown. We have determined the crystal structure of one of the proteins coded by the cag genes, CagD, in two crystal forms. We show that the protein is a covalent dimer in which each monomer folds as a single domain that is composed of five β-strands and three α-helices. Our data show that in addition to a cytosolic pool, CagD partially associates with the inner membrane, where it may be exposed to the periplasmic space. Furthermore, CagA tyrosine phosphorylation and interleukin-8 assays identified CagD as a crucial component of the T4SS that is involved in CagA translocation into host epithelial cells; however, it does not seem absolutely necessary for pilus assembly. We have also identified significant amounts of CagD in culture supernatants, which are not a result of general bacterial lysis. Since this localization was independent of the various tested cag mutants, our findings may indicate that CagD is released into the supernatant during host cell infection and then binds to the host cell surface or is incorporated in the pilus structure. Overall, our results suggest that CagD may serve as a unique multifunctional component of the T4SS that may be involved in CagA secretion at the inner membrane and may localize outside the bacteria to promote additional effects on the host cell.     

Functions of amine oxidases in plant development and defence

Copper amine oxidases and flavin-containing amine oxidases catalyse the oxidative de-amination of polyamines, which are ubiquitous compounds essential for cell growth and proliferation. Far from being only a means of degrading cellular polyamines and, thus, contributing to polyamine homeostasis, amine oxidases participate in important physiological processes through their reaction products. In plants, the production of hydrogen peroxide (H(2)O(2)) deriving from polyamine oxidation has been correlated with cell wall maturation and lignification during development as well as with wound-healing and cell wall reinforcement during pathogen invasion. As a signal molecule, H(2)O(2) derived from polyamine oxidation mediates cell death, the hypersensitive response and the expression of defence genes. Furthermore, aminoaldehydes and 1,3-diaminopropane from polyamine oxidation are involved in secondary metabolite synthesis and abiotic stress tolerance.     

pH-dependent redox and CO binding properties of chelated protoheme-<Emphasis Type="SmallCaps">l</Emphasis>-histidine and protoheme-glycyl-<Emphasis Type="SmallCaps">l</Emphasis>-histidine complexes

The pH dependence of redox properties, spectroscopic features and CO binding kinetics for the chelated protohemin-6(7)-l-histidine methyl ester (heme-H) and the chelated protohemin-6(7)-glycyl-l-histidine methyl ester (heme-GH) systems has been investigated between pH 2.0 and 12.0. The two heme systems appear to be modulated by four protonating groups, tentatively identified as coordinated H₂O, one of heme’s propionates, Nε of the coordinating imidazole, and the carboxylate of the histidine residue upon hydrolysis of the methyl ester group (in acid medium). The pK _a values are different for the two hemes, thus reflecting structural differences. In particular, the different strain at the Fe–N _ε bond, related to the different length of the coordinating arm, results in a dramatic alteration of the bond strength, which is much smaller in heme-H than in heme-GH. It leads to a variation in the variation of the pK a for the protonation of the N _ε of the axial imidazole as well as in the proton-linked behavior of the other protonating groups, envisaging a cross-talk communication mechanism among different groups of the heme, which can be operative and relevant also in the presence of the protein matrix. Electronic Supplementary Material Supplementary material is available for this article at and is accessible for authorized users.     

Hypoxia-induced mitogenic factor has proangiogenic and proinflammatory effects in the lung via VEGF and VEGF receptor-2

From a mouse model of hypoxia-induced pulmonary hypertension, we previously found a highly upregulated protein in the lung that we named hypoxia-induced mitogenic factor (HIMF), also known as found in inflammatory zone 1 (FIZZ1), and resistin-like molecule alpha (RELMalpha). However, the mechanisms of HIMF in the pulmonary vascular remodeling remain unknown. We now demonstrate that HIMF promoted cell proliferation, migration, and the production of vascular endothelial growth factor (VEGF) and monocyte chemotactic protein-1 (MCP-1) in pulmonary endothelial cells as well as the production of reactive oxygen species in murine monocyte/macrophage cells. HIMF-induced CD31-positive cell infiltrate in in vivo Matrigel plugs was significantly suppressed by VEGF receptor-2 (VEGFR2) blockade. In ex vivo studies, HIMF stimulated the production of VEGF, MCP-1, and stromal cell-derived factor-1 (SDF-1) in the lung resident cells, and VEGFR2 neutralization significantly suppressed HIMF-induced MCP-1 and SDF-1 production. Furthermore, intravenous injection of HIMF showed marked increase of CD68-positive inflammatory cells in the lungs, and these events were attenuated by VEGFR2 neutralization. Intravenous injection of HIMF also downregulated the expression of VEGFR2 in the lung. These results suggest that HIMF plays critical roles in pulmonary inflammation as well as angiogenesis.