Neuroprotective Effects of Testosterone in the Hypothalamus of an Animal Model of Metabolic Syndrome

Metabolic syndrome (MetS) is known to be associated to inflammation and alteration in the hypothalamus, a brain region implicated in the control of several physiological functions, including energy homeostasis and reproduction. Previous studies demonstrated the beneficial effects of testosterone treatment (TTh) in counteracting some MetS symptoms in both animal models and clinical studies. This study investigated the effect of TTh (30 mg/kg/week for 12 weeks) on the hypothalamus in a high-fat diet (HFD)-induced animal model of MetS, utilizing quantitative RT-PCR and immunohistochemical analyses. The animal model recapitulates the human MetS features, including low testosterone/gonadotropin plasma levels. TTh significantly improved MetS-induced hypertension, visceral adipose tissue accumulation, and glucose homeostasis derangements. Within hypothalamus, TTh significantly counteracted HFD-induced inflammation, as detected in terms of expression of inflammatory markers and microglial activation. Moreover, TTh remarkably reverted the HFD-associated alterations in the expression of important regulators of energy status and reproduction, such as the melanocortin and the GnRH-controlling network. Our results suggest that TTh may exert neuroprotective effects on the HFD-related hypothalamic alterations, with positive outcomes on the circuits implicated in the control of energy metabolism and reproductive tasks, thus supporting a possible role of TTh in the clinical management of MetS.     

Synthesis and Evaluation of Voltage-Gated Sodium Channel Blocking Pyrroline Derivatives Endowed with Both Antiarrhythmic and Antioxidant Activities

Under the hypothesis that cardioprotective agents might benefit from synergism between antiarrhythmic activity and antioxidant properties, a small series of mexiletine analogues were coupled with the 2,2,5,5-tetramethylpyrroline moiety, known for its antioxidant effect, in order to obtain dual-acting drugs potentially useful in the protection of the heart against post-ischemic reperfusion injury. The pyrroline derivatives reported herein were found to be more potent as antiarrhythmic agents than mexiletine and displayed antioxidant activity. The most interesting tetramethylpyrroline congener, a tert-butyl-substituted analogue, was at least 100 times more active as an antiarrhythmic than mexiletine.     

High-Fat Diet Leads to Reduced Protein O-GlcNAcylation and Mitochondrial Defects Promoting the Development of Alzheimer’s Disease Signatures

The disturbance of protein O-GlcNAcylation is emerging as a possible link between altered brain metabolism and the progression of neurodegeneration. As observed in brains with Alzheimer’s disease (AD), flaws of the cerebral glucose uptake translate into reduced protein O-GlcNAcylation, which promote the formation of pathological hallmarks. A high-fat diet (HFD) is known to foster metabolic dysregulation and insulin resistance in the brain and such effects have been associated with the reduction of cognitive performances. Remarkably, a significant role in HFD-related cognitive decline might be played by aberrant protein O-GlcNAcylation by triggering the development of AD signature and mitochondrial impairment. Our data support the impairment of total protein O-GlcNAcylation profile both in the brain of mice subjected to a 6-week high-fat-diet (HFD) and in our in vitro transposition on SH-SY5Y cells. The reduction of protein O-GlcNAcylation was associated with the development of insulin resistance, induced by overfeeding (i.e., defective insulin signaling and reduced mitochondrial activity), which promoted the dysregulation of the hexosamine biosynthetic pathway (HBP) flux, through the AMPK-driven reduction of GFAT1 activation. Further, we observed that a HFD induced the selective impairment of O-GlcNAcylated-tau and of O-GlcNAcylated-Complex I subunit NDUFB8, thus resulting in tau toxicity and reduced respiratory chain functionality respectively, highlighting the involvement of this posttranslational modification in the neurodegenerative process.     

The AFLATOX® Project: Approaching the Development of New Generation,Natural-Based Compounds for the Containment of the Mycotoxigenic Phytopathogen Aspergillus flavus and Aflatoxin Contamination

The control of the fungal contamination on crops is considered a priority by the sanitary authorities of an increasing number of countries, and this is also due to the fact that the geographic areas interested in mycotoxin outbreaks are widening. Among the different pre- and post-harvest strategies that may be applied to prevent fungal and/or aflatoxin contamination, fungicides still play a prominent role; however, despite of countless efforts, to date the problem of food and feed contamination remains unsolved, since the essential factors that affect aflatoxins production are various and hardly to handle as a whole. In this scenario, the exploitation of bioactive natural sources to obtain new agents presenting novel mechanisms of action may represent a successful strategy to minimize, at the same time, aflatoxin contamination and the use of toxic pesticides. The Aflatox^® Project was aimed at the development of new-generation inhibitors of aflatoxigenic Aspergillus spp. proliferation and toxin production, through the modification of naturally occurring molecules: a panel of 177 compounds, belonging to the thiosemicarbazones class, have been synthesized and screened for their antifungal and anti-aflatoxigenic potential. The most effective compounds, selected as the best candidates as aflatoxin containment agents, were also evaluated in terms of cytotoxicity, genotoxicity and epi-genotoxicity to exclude potential harmful effect on the human health, the plants on which fungi grow and the whole ecosystem.     

Recommending multimedia visiting paths in cultural heritage applications

The valorization and promotion of worldwide Cultural Heritage by the adoption of Information and Communication Technologies represent nowadays some of the most important research issues with a large variety of potential applications. This challenge is particularly perceived in the Italian scenario, where the artistic patrimony is one of the most diverse and rich of the world, able to attract millions of visitors every year to monuments, archaeological sites and museums. In this paper, we present a general recommendation framework able to uniformly manage heterogeneous multimedia data coming from several web repositories and to provide context-aware recommendation techniques supporting intelligent multimedia services for the users—i.e. dynamic visiting paths for a given environment. Specific applications of our system within the cultural heritage domain are proposed by means of real case studies in the mobile environment related both to an outdoor and indoor scenario, together with some results on user’s satisfaction and system accuracy.     

Sorafenib delivery nanoplatform based on superparamagnetic iron oxide nanoparticles magnetically targets hepatocellular carcinoma

Currently,sorafenib is the only systemic therapy capable of increasing overall survival of hepatocellular carcinoma patients.Unfortunately,its side effects,particularly its overall toxicity,limit the therapeutic response that can be achieved.Superparamagnetic iron oxide nanoparticles (SPIONs) are very attractive for drug delivery because they can be targeted to specific sites in the body through application of a magnetic field,thus improving intratumoral accumulation and reducing adverse effects.Here,nanoformulations based on polyethylene glycol modified phospholipid micelles,loaded with both SPIONs and sorafenib,were successfully prepared and thoroughly investigated by complementary techniques.This nanovector system provided effective drug delivery,had an average hydrodynamic diameter of about 125 nm,had good stability in aqueous medium,and allowed controlled drug loading.Magnetic analysis allowed accurate determination of the amount of SPIONs embedded in each micelle.An in vitro system was designed to test whether the SPION micelles can be efficiently held using a magnetic field under typical flow conditions found in the human liver.Human hepatocellular carcinoma (HepG2) cells were selected as an in vitro system to evaluate tumor cell targeting efficacy of the superparamagnetic micelles loaded with sorafenib.These experiments demonstrated that this delivery platform is able to enhance sorafenib's antitumor effectiveness by magnetic targeting.The magnetic nanovectors described here represent promising candidates for targeting specific hepatic tumor sites,where selective release of sorafenib can improve its efficacy and safety profile.     

Preface: Volume 16, Issue 2

This volume contains the Proceedings of the fifth EXPRESS workshop. The workshop was held in Nice, France, on 7 September 1998, as a satellite event to CONCUR '98.The EXPRESS workshops aim at bringing together researchers interested in the relations between various formal systems, particularly in the field of Concurrency. More specifically, they focus on the comparison between programming concepts (such as concurrent, functional, imperative, logic and object-oriented programming) and between mathematical models of computation (such as process algebras, Petri nets, event structures, modal logics, rewrite systems etc.) on the basis of their relative expressive power.These workshops were originally held as meetings of the HCM project EXPRESS, which has been active with the same focus from January 1994 till December 1997. The first three workshops were held respectively in Amsterdam (1994, chaired by Frits Vaandrager), Tarquinia (1995, chaired by Rocco de Nicola), and Dagstuhl (1996, chaired by Ursula Goltz, Frits Vaandrager and Rocco de Nicola). The fourth workshop, which took place in Santa Margherita Ligure in 1997 and was co-chaired by Catuscia Palamidessi and Joachim Parrow, was organized as a conference with a call for papers and a significant attendance from outside the project. The fifth workshop, EXPRESS '98, was again organised as a (one day) conference, and was also meant as an occasion to discuss on the inheritance of the Express project and possible directions of future research. We had 17 submissions, out of which we selected 7 for inclusion in these proceedings (41%). Additionally, this collection contains the contribution of the two invited speakers, Matthew Hennessy (University of Sussex, UK) and P.S. Thiagarajan (SPIC Mathematical Institute, IN).We would like to thank the authors of the submitted papers, the invited speakers, and the members of the program committee for their contribution to both the meeting and this volume. We also would like to thank INRIA for their help with the local organization, and Michael Mislove for his help with the editing of the proceedings.

EXPRESS '98 Programme Committee
Ilaria Castellani (co-chair, INRIA)	Catuscia Palamidessi (co-chair, PSU)
Luca Aceto (Aalborg Univ.)	Roberto Amadio (Univ. Marseille)
Eike Best (Oldenburg Univ.)	Steve Brookes (CMU)
Philippe Darondeau (INRIA)	Rocco De Nicola (Univ. Firenze)
Jan Willem Klop (CWI)	Patrick Lincoln (SRI)
Frits Vaandrager (Nijmegen Univ.)	Glynn Winskel (Aarhus Univ.)

Full-size table

17 October 1998, Ilaria Castellani and Catuscia Palamidessi     

Knowledge Management in Locating the Patient in an Emergency Medical Service in Italy

This study examines an Emergency Medical Service in order to analyze the composite set of activities and instruments directed at locating the patient. The good management of information about the location of the emergency is highly relevant for a reliable rescue service, but this information depends on knowledge of the territory that is socially distributed between EMS operators and callers. Accordingly, the decision-making process often has to go beyond the emergency service protocols, engaging the operator in undertaking an open negotiation in order to transform the caller’s role from layman to “co-worker”. The patient’s location turns out to be an emerging phenomenon, collaborative work based on knowledge management involving two communities—the callers and the EMS operators—that overlap partially. Drawing examples from emergency calls, the study analyzes the practice of locating a patient as a complex and multi-layered process, highlighting the role played by new and old technologies (the information system and the paper maps) in this activity. We argue that CSCW technologies enable the blended use of different kinds of instruments and support an original interconnection between the professional localization systems and the public’s way of defining a position.     

Self-adaptation and secure information flow in multiparty communications

We present a comprehensive model of structured communications in which self-adaptation and security concerns are jointly addressed. More specifically, we propose a model of multiparty, self-adaptive communications with access control and secure information flow guarantees. In our model, multiparty protocols (choreographies) are described as global types; security violations occur when process implementations of protocol participants attempt to read or write messages of inappropriate security levels within directed exchanges. Such violations trigger adaptation mechanisms that prevent the violations to occur and/or to propagate their effect in the choreography. Our model is equipped with local and global adaptation mechanisms for reacting to security violations of different gravity; type soundness results ensure that the overall multiparty protocol is still correctly executed while the system adapts itself to preserve the participants’ security.