Mutual Inductance Route to Paramagnetic Meissner Effect in 2D Josephson Junction Arrays

We simulate two-dimensional Josephson junction arrays, including full mutual- inductance effects, as they are cooled below the transition temperature in a magnetic field. We show numerical simulations of the array magnetization as a function of position, as detected by a scanning SQUID which is placed at a fixed height above the array. The calculated magnetization images show striking agreement with the experimental images obtained by A. Nielsen et al. The average array magnetization is found to be paramagnetic for many values of the applied field, confirming that paramagnetism can arise from magnetic screening in multiply-connected superconductors without the presence of d-wave superconductivity.Comment: REVTeX 3.1, 5 pages, 5 figure

Ras-pathway has a dual role in yeast galactose metabolism

In the yeast Saccharomyces cerevisiae the genes involved in galactose metabolism (GAL1,7,10) are transcriptionally activated more than a 1000-fold in the presence of galactose as the sole carbon source in the culture media. In the present work, we monitored the activity of the GAL10 gene promoter in different Ras-cAMP genetic backgrounds. We demonstrate that overexpression of C-terminus of the nucleotide exchange factor Cdc25p stimulates GAL10 transcription in yeast strains carrying the contemporary deletion of both RAS genes. Moreover, the deletion of the chromosomal CDC25 gene provokes impaired growth on galactose based media in yeast strain lacking both RAS genes and adenylate cyclase (whose viability is assured by the presence of the Bcy1-11 allele). Surprisingly, reconstitution of the Ras-pathway inhibits GAL10-promoter activation. Activation of GAL10 gene promoter is indeed possible in the presence of Ras protein but only in strains with chromosomal deletion of adenylate cyclase. These results indicate a dual role of Ras-pathway on galactose metabolism and suggest that Cdc25p has a Ras-independent role in cellular metabolism

Application of an immunoproteomic approach to detect anti-profilin antibodies in sera of paritaria judaica allergic patients

Pollen from grasses, weeds, and trees constitutes one of the main sources of inhalant allergens frequently associated with seasonal patterns of allergic diseases. Pollen allergens show some analogies in the amino acids sequence which determine immunological similarity and cross reactivity. Parietaria judaica (P.j) pollen represents one of the main sources of allergens in the Mediterranean area and its major allergens have already been identified (Par j 1 and Par j 2). Recently, has been also described a minor allergen, profilin (Par j 3), an allergen present in pollen of trees, grasses and weeds. Allergenic plant profilins constitute a highly conserved family with sequence identities of 70% to 85% responsible for a wide range of cross-reactivity among pollens and plant foods. In this work we use an immunoproteomic approach to detect IgE antibodies against profilin in serum of P.j allergic patients

Localization of antimicrobial peptides in the tunic of Ciona intestinalis ( Ascidiacea, Tunicata) and their involvement in local inflammatory-like reactions

Tunicates comprising a wide variety of different species synthesize antimicrobial peptides as important effector molecules of the innate immune system. Recently, two putative gene families coding for antimicrobial peptides were identified in the expressed sequence tag database of the tunicate Ciona intestinalis. Two synthetic peptides representing the cationic core region of one member of each of the families displayed potent antibacterial and antifungal activities. Moreover, the natural peptides were demonstrated to be synthesized and stored in distinct hemocyte types. Here, we investigated the presence of these natural peptides, namely Ci-MAM-A and Ci-PAP-A, in the tunic of C. intestinalis considering that the ascidian tunic is a body surface barrier exposed to constant microbial assault. Furthermore, as the tunic may represent a major route of entry for pathogen invasion after its damage we monitored the location of these peptides upon a local inflammatory-like reaction induced by injection of foreign cells. Using immunocytochemistry and electron microscopy both peptides were localized to the tunic and were massively present in granulocytes of inflamed tissue. Conclusively, antimicrobial peptides may constitute a chemical barrier within the tunic of urochordates

Exosomes as Intercellular Signaling Organelles Involved in Health and Disease: Basic Science and Clinical Applications

Cell to cell communication is essential for the coordination and proper organization of different cell types in multicellular systems. Cells exchange information through a multitude of mechanisms such as secreted growth factors and chemokines, small molecules (peptides, ions, bioactive lipids and nucleotides), cell-cell contact and the secretion of extracellular matrix components. Over the last few years, however, a considerable amount of experimental evidence has demonstrated the occurrence of a sophisticated method of cell communication based on the release of specialized membranous nano-sized vesicles termed exosomes. Exosome biogenesis involves the endosomal compartment, the multivesicular bodies (MVB), which contain internal vesicles packed with an extraordinary set of molecules including enzymes, cytokines, nucleic acids and different bioactive compounds. In response to stimuli, MVB fuse with the plasma membrane and vesicles are released in the extracellular space where they can interact with neighboring cells and directly induce a signaling pathway or affect the cellular phenotype through the transfer of new receptors or even genetic material. This review will focus on exosomes as intercellular signaling organelles involved in a number of physiological as well as pathological processes and their potential use in clinical diagnostics and therapeutics

CarboxyAmido-Triazole Orotate inhibits the growth of Imatinib-resistant chronic myeloid leukaemia cells and modulates exosomes-stimulated angiogenesis

Chronic myelogenous leukemia is a myeloproliferative disorder characterized by the t(9:22) (q34:q11) reciprocal chromosomal translocation, resulting in the expression of the chimeric Bcr–Abl oncoprotein with constitutive tyrosine kinase activity. Deregulated Bcr–Abl induces the hyperactivation of various signalling pathways that promote cell growth, suppress apoptosis and alter cell adhesion. Bcr-Abl has also been involved in VEGF-mediated angiogenesis in CML and evidence indicates that the formation of new vessels plays an important role in the development and progression of CML. Imatinib mesylate (IM) is a selective well tolerated inhibitor of the Bcr–Abl tyrosine kinase that has significantly improved the prognosis of patients with chronic phase CML. Despite this remarkable progress, a major problem associated with the administration of imatinib is acquired resistance. Bcr-Abl gene amplification, increased expression of Bcr–Abl protein, point mutations in the Bcr–Abl tyrosine kinase domain have been reported as mechanisms of resistance to imatinib. Therefore, there is an urgent need for new anticancer agents and combinations that could improve responses and survival rates for CML. Recent studies from our laboratory have shown that addition of carboxyamidotriazole (CAI), an inhibitor of calcium-mediated signal transduction, to imatinib resistant human CML cells induces a marked decrease in cell viability and augmented apoptosis, events associated with downregulation of Bcr–Abl protein and inhibition of tyrosine phosphorylation of Bcr–Abl, STAT5, CrkL. Carboxyamidotriazole Orotate (CTO), is a derivate of CAI that has been developed at Tactical Therapeutics. CTO has a higher bioavailability and efficacy with respect to the parental compound. Exosomes are small vesicles of 40-100 nm diameter that are initially formed within the endosomal compartment and are secreted when a multivesicular body (MVB) fuses with the plasma membrane. These vesicles are released by many cell types including cancer cells and are considered messengers in intercellular communication. The exact function of exosomes in malignant cells has yet to be elucidated, but investigation has suggested roles in cell-to-cell communication, tumor-stroma interaction, and antigen presentation, thus potentially affecting cancer progression at different steps. Recent studies from our laboratory suggest that exosomes released from IM-sensitive CML cells directly affect endothelial cells modulating the process of neovascularization. Our data show that CTO is able to inhibit both in vitro and in vivo the growth of imatinib-resistant CML cells and to affect tumor microenvironment by modulating exosome-stimulated angiogenesis. CTO may be effective in targeting both cancer cell growth and the tumor microenvironment, thus suggesting a potential therapeutic utility in the treatment of leukemia patients

Exosome-mediated crosstalk between chronic myelogenous leukemia cells and human bone marrow stromal cells triggers an interleukin 8-dependent survival of leukemia cells

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by the Bcr–Abl oncoprotein with constitutive tyrosine kinase activity. Exosomes are nanovesicles released by cancer cells that are involved in cell-to-cell communication thus potentially affecting cancer progression. It is well known that bone marrow stromal microenvironment contributes to disease progression through the establishment of a bi-directional crosstalk with cancer cells. Our hypothesis is that exosomes could have a functional role in this crosstalk. Interleukin-8 (IL 8) is a proinflammatory chemokine that activates multiple signalling pathways downstream of two receptors (CXCR1 and CXCR2). We demonstrated that exosomes released from CML cells stimulate bone marrow stromal cells to produce IL 8 that, in turn, is able to modulate both in vitro and in vivo the leukemia cell malignant phenotype

Exosomal shuttling of miR-126 in endothelial cells modulates adhesive and migratory abilities of chronic myelogenous leukemia cells

BACKGROUND: Recent findings indicate that exosomes released from cancer cells contain microRNAs (miRNAs) that may be delivered to cells of tumor microenvironment. RESULTS: To elucidate whether miRNAs secreted from chronic myelogenous leukemia cells (CML) are shuttled into endothelial cells thus affecting their phenotype, we first analysed miRNAs content in LAMA84 exosomes. Among the 124 miRNAs identified in LAMA84 exosomes, we focused our attention on miR-126 which was found to be over-overexpressed in exosomes compared with producing parental cells. Transfection of LAMA84 with Cy3-labelled miR-126 and co-culture of leukemia cells with endothelial cells (EC) confirmed that miR-126 is shuttled into HUVECs. The treatment of HUVECs with LAMA84 exosomes for 24 hours reduced CXCL12 and VCAM1 expression, both at the mRNA and protein level, and negatively modulated LAMA84 motility and cells adhesion. Transfection in HUVECs of miR-126 inhibitor reversed the decrease of CXCL12 and restored the motility and adhesion of LAMA84 cells while the over-expression of miR-126, showed opposite effects. CONCLUSION: Our results show that the miR-126 shuttled by exosomes is biologically active in the target cells, and support the hypothesis that exosomal miRNAs have an important role in tumor-endothelial crosstalk occurring in the bone marrow microenvironment, potentially affecting disease progression