1,721,281 research outputs found
Antiprotozoal activity of novel diaryliminophenazines
Full text linkRecently, we synthesized a set of novel iminofenazines bearing a bicyclic basic head linked through an alkyl chain to the imino nitrogen in position 3 on the phenazine nucleus (Fig.1).
Most of these compounds inhibited the growth of different species of Leishmania promastigotes as well as of chloroquine sensitive (CQ-S) and chloroquine resistant (CQ-R) strains of P. falciparum with IC50 in the submicromolar range. Unfortunately, these compounds exhibited also a significant toxicity against the human endothelial cell line HMEC-1 with IC50 in the low micromolar range and with a consequent low selectivity index.
Figure1.Structures of the previously synthesized compounds.
To continue the studies on the antiprotozoal potentialities of this class of compounds and with the aim to improve their activity and selectivity on protozoa, we have now synthesized novel compounds characterized by the replacement of the aniline moiety in pos. 2 of the phenazine nucleus with an aminopyridine, and/or by a quaternarization of the basic nitrogen in the side chain with a methyl group (Fig.2).
Figure 2. Structures of the new compounds synthesized.
The in vitro activity of the new compounds on Leishmania promastigotes and on CQ-S and CQ-R strains of P. falciparum, as well as on the HMEC-1 cell line will be presented and discussed.
References
[1] A. Barteselli, M. Gavazzi, N. Basilico, S. Parapini, D. Taramelli, A. Sparatore. Clofazimine analogs with antileishmanial and antimalarial activities. XXII National Meeting on Medicinal Chemistry, Roma 2013
Asynchronous multi-robot patrolling against intrusions in arbitrary topologies
No full textUse of game theoretical models to derive randomized mobile robot patrolling strategies has recently received a growing attention. We focus on the problem of patrolling environments with arbitrary topologies using multiple robots. We address two important issues currently open in the literature. We determine the smallest number of robots needed to patrol a given environment and we compute the optimal patrolling strategies along several coordination dimensions. Finally, we experimentally evaluate the proposed techniques. Copyright © 2010, Association for the Advancement of Artificial Intelligence (www.aaai.org)
Methods for finding leader-follower equilibria with multiple followers : extended abstract
No full textLeader-follower (LF) equilibria play a central role in several applications of game theory. In spite of this, the literature only presents sporadic results for the case with two or more followers. In this work, we address the problem of computing LF equilibria in this setting, assuming that the followers play a Nash Equilibrium after the leader’s commitment
Deploying teams of heterogeneous UAVs in cooperative two-level surveillance missions
No full textWe consider the problem of providing surveillance to a grid area using multiple heterogeneous UAVs, named sentinels and searchers, with complementary sensing and actuation capabilities. We consider probabilistic attacks and we analyze the expected performance with respect to the team deployment. We then introduce the problem of finding minmax deployments that result in the most desirable worst case performance caused by an attack. We present an algorithm to compute deployments while trading off solution's quality and computational effort and we qualitatively and quantitatively analyze it
Macrophage preconditioning with synthetic malaria pigment reduces cytokine production via heme iron-dependent oxidative stress
Full text linkHemozoin (malaria pigment), a polymer of hematin (ferri-protoporphyrin IX) derived from hemoglobin ingested by intraerythrocytic plasmodia, modulates cytokine production by phagocytes. Mouse peritoneal macrophages (PM) fed with synthetic beta-hematin (BH), structurally identical to native hemozoin, no longer produce tumor necrosis factor alpha (TNFalpha) and nitric oxide (NO) in response to lipopolysaccharide (LPS). Impairment of NO synthesis is due to inhibition of inducible nitric oxide synthase (iNOS) production. BH-mediated inhibition of PM functions cannot be ascribed to iron release from BH because neither prevention by iron chelators nor down-regulation of iron-regulatory protein activity was detected. Inhibition appears to be related to pigment-induced oxidative stress because (a) thiol compounds partially restored PM functions, (b) heme oxygenase (HO-1) and catalase mRNA levels were up-regulated, and (c) free radicals production increased in BH-treated cells. The antioxidant defenses of the cells determine the response to BH: microglia cells, which show a lower extent of induction of HO-1 and catalase mRNAs and lower accumulation of oxygen radicals, are less sensitive to the inhibitory effect of BH on cytokine production. Results indicate that BH is resistant to degradation by HO-1 and that heme-iron mediated oxidative stress may contribute to malaria-induced immunosuppression. This study may help correlate the different clinical manifestations of malaria, ranging from uncomplicated to severe disease, with dysregulation of phagocyte functions and promote better therapeutic strategies to counteract the effects of hemozoin accumulation
Synergistic and antagonistic interactions between haemozoin and bacterial endotoxin on human and mouse macrophages
No full textHaemozoin (malaria pigment) is a birefringent crystalline material made of Fe (III) Protoporphyrin IX dimers that derives from the degradation of haemoglobin by intraerythrocytic Plasmodia. At schizont rupture, it accumulates indigested inside phagocytic cells altering their immunological properties. Both pro-inflammatory and immunosuppressive activities have been associated with pigment-fed monocyte-macrophages or dendritic cells. These conflicting results were attributed to the source of macrophages or the different preparations of pigment. However, the interactions of malaria pigment with other phagocytes stimuli, such as bacterial endotoxin (LPS) or interferon-gamma have not been fully analysed, yet. The purpose of this study was to compare the immunological properties of native haemozoin (HZ), freshly extracted from Plasmodium falciparum cultures, versus beta-haematin (BH), the synthetic crystals identical to native haemozoin, and to evaluate the relationship between haemozoin and endotoxin on the immune response of different macrophages populations. The results indicate that the iron-porphyrin moiety of both native and synthetic pigment can exert either a synergistic or antagonistic effect with LPS that is related to the length and sequence of treatment, the source of macrophages and is associated with the generation of oxidative stress. These data rise the question of whether and how in vivo concomitant gram(-) bacteremia may affect the pathogenesis and/or the immune response of malaria infections and vice versa
Haem metabolism in Plasmodium falciparum : consequences for the parasites and host cells
No full textAutomated Abstractions for Patrolling Security Games
Full text linkRecently, there has been a significant interest in studying security games to provide tools for addressing resource allocation problems in security applications. Patrolling security games (PSGs) constitute a special class of security games wherein the resources are mobile. One of the most relevant open problems in security games is the design of scalable algorithms to tackle realistic scenarios. While the literature mainly focuses on heuristics and decomposition techniques (e.g., double oracle), in this paper we provide, to the best of our knowledge, the first study on the use of abstractions in security games (specifically for PSGs) to design scalable algorithms. We define some classes of abstractions and we provide parametric algorithms to automatically generate abstractions. We show that abstractions allow one to relax the constraint of patrolling strategies' Markovianity (customary in PSGs) and to solve large game instances. We additionally pose the problem to search for the optimal abstraction and we develop an anytime algorithm to find it
Involvement of NOD2 in macrophage response to leishmania tropica infection
No full textBACKGROUND-AIM Leishmaniasis is a protozoan disease caused by parasites belonging to the genus Leishmania. In the human host, these parasites invade macrophages where they develop into intracellular amastigotes and multiply within phagolysosomes. Host cells can control the infection initially through the triggering of innate immune responses. NOD-like receptors (NLRs) are a family of innate immune cytosolic receptors able to recognize pathogen-associated molecular patterns. NOD1 and NOD2 detect pathogens that are able to invade and multiply intracellularly. Once stimulated, these receptors induce the activation of NF-κB and MAPKs, which lead to the transcription of genes involved in inflammation and immune responses. The aim of this work was to evaluate the role of NOD2 in some innate immune responses of macrophages infected with L. tropica. In particular, the production of TNF-a, or nitric oxide (NO), and the expression of inducible NO synthase (iNOS) were evaluated METHODS Immortalized bone marrow-derived macrophages (BMDM) from wild type (WT) C57Bl/6 or knockout (KO) mice for NOD2 were used. The levels of TNF-a released into the supernatants of BMDM-WT or -NOD2-KO treated with L. tropica were measured by ELISA. Also, the presence of nitrite was evaluated, through the Griess test, as an indication of nitric oxide (NO) production. Finally, protein and gene expression levels of iNOS were retrieved by Western blot analysis and realtime PCR, respectively. RESULTS The involvement of NOD2 in BMDM treated with L. tropica was elucidated as the levels of TNF-a or NO released from BMDM-WT infected with L. tropica were significantly higher compared to the BMDM-NOD2-KO. On the other side, the expression of iNOS (RNA and protein) was higher in BMDM-WT treated with L. tropica than in BMDM-NOD2-KO. CONCLUSIONS Altogether, these data indicated a crucial role of NOD2 for these innate immune responses of BMDM infected with L.tropica
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