Social isolation blunted the response of mesocortical dopaminergic neurons to chronic ethanol voluntary intake

Previous studies have shown that stress can increase the response of mesolimbic dopaminergic neurons to acute administration of drugs of abuse included ethanol. In this study, we investigated the possible involvement of the mesocortical dopaminergic pathway in the development of ethanol abuse under stress conditions. To this aim we trained both socially isolated (SI) and group housed (GH) rats to self administer ethanol which was made available only 2 ha day (from 11:00 to 13:00 h). Rats have been trained for 3 weeks starting at postnatal day 35. After training, rats were surgically implanted with microdialysis probes under deep anesthesia, and 24 hlater extracellular dopamine concentrations were monitored in medial prefrontal cortex (mPFC) for the 2 hpreceding ethanol administration (anticipatory phase), during ethanol exposure (consummatory phase) and for 2 hafter ethanol removal. Results show that, in GH animals, dopamine extracellular concentration in the mPFC increased as early as 80 min before ethanol presentation (+50% over basal values) and remained elevated for 80 min during ethanol exposure. In SI rats, on the contrary, dopamine extracellular concentration did not show any significant change at any time point. Ethanol consumption was significantly higher in SI than in GH rats. Moreover, mesocortical dopaminergic neurons in SI animals also showed a decreased sensitivity to an acute administration of ethanol with respect to GH rats. Our results show that prolonged exposure to stress, as in social isolation, is able to induce significant changes in the response of mesocortical dopaminergic neurons to ethanol exposure and suggest that these changes might play an important role in the compulsivity observed in ethanol addictio

Distributed Current Flow Betweeness Centrality

—The computation of nodes centrality is of great importance for the analysis of graphs. The current flow betweenness is an interesting centrality index that is computed by considering how the information travels along all the possible paths of a graph. The current flow betweenness exploits basic results from electrical circuits, i.e. Kirchhoff’s laws, to evaluate the centrality of vertices. The computation of the current flow betweenness may exceed the computational capability of a single machine for very large graphs composed by millions of nodes. In this paper we propose a solution that estimates the current flow betweenness in a distributed setting, by defining a vertex-centric, gossip-based algorithm. Each node, relying on its local information, in a selfadaptive way generates new flows to improve the betweenness of all the nodes of the graph. Our experimental evaluation shows that our proposal achieves high correlation with the exact current flow betweenness, and provides a good centrality measure for large graphs

Neurosteroidi: i modulatori endogeni delle emozioni

The discovery that facilitation or inhibition of γ aminobutyric acid (GABA)-mediated neurotransmission results in anxiolytic versus anxiogenic, hypnotic versus somnolitic, and anticonvulsant versus convulsant effects, respectively, provided important early insight into the physiology and pharmacology of central GABAergic transmission. This realization, together with subsequent evidence that high-affinity recognition sites for positive and negative allosteric modulators of GABAA receptors are located on these GABA-gated Cl– channels, led to the concept that GABAA receptors contribute directly not only to the pharmacology but also to the neurobiology and physiopathology of a variety of neurological and psychiatric diseases characterized by changes in emotional state, sleep pattern, or neuronal excitability. These findings have suggested the hypothesis that the brain and peripheral organs in mammals might produce endogenous compounds that selectively modulate central GABAA receptor function. Evidence directly supporting this hypothesis has been provided over the last decade by the discovery that steroid hormones synthesized in the brain or in peripheral organs are among the most selective, potent, and efficacious allosteric modulators of GABAA receptors. Neurosteroids are steroid derivatives that are synthesized de novo from cholesterol in the central nervous system (CNS), some of which modulate GABAA receptor function with potencies and efficacies similar to or greater than those of benzodiazepines and barbiturates. These molecules have thus been suggested to be the endogenous modulators of GABAA receptor–mediated neurotransmission. In fact some of these molecules have the capability to modulate synaptic activity by binding to membrane sites associated with ligand-gated ionotropic receptors including GABAA receptors. Here we summarize some of the most recent evidences obtained by our and other laboratories pertaining the role of two neuroactive steroids allopregnanolone (AP) and tetrahydrodeoxycorticosterone (THDOC) actives in modulating the function and plasticity of GABAA receptors in nature

GROUP: A Gossip Based Building Community Protocol

The detection of communities of peers characterized by similar interests is currently a challenging research area. To ease the diffusion of relevant data to interested peers, similarity based overlays define links between similar peers by exploiting a similarity function. However, existing solutions neither give a clear definition of peer communities nor define a clear strategy to partition the peers into communities. As a consequence, the spread of the information cannot be confined within a well defined region of an overlay. This paper proposes a distributed protocol for the detection of communities in a P2P network. Our approach is based on the definition of a distributed voting algorithm where each peer chooses the more similar peers among those in a limited neighbourhood range. The identifier of the most representative peer is exploited to identify a community. The paper shows the effectiveness of our approach by presenting a set of experimental results

Promising inhibition of diabetes-related enzymes and antioxidant properties of Ptilostemon casabonae leaves extract

Type 2 diabetes (T2D) is a progressive metabolic disorder of glucose metabolism. One of the therapeutic approaches for the treatment of T2D is reducing postprandial hyperglycaemia through inhibition of the digestive enzymes α-glucosidase and α-amylase. In this context, aimed at identifying natural products endowed with anti-T2D potential, we focused on Ptilostemon casabonae (L.) Greuter, a species belonging to Asteraceae family. Enzymatic inhibition, antioxidant activity, phenolic composition and cellular assays were performed. This study revealed that the P. casabonae hydroalcoholic extract exerts a potent inhibitory activity against α-glucosidase. This activity is supported by an antioxidant effect, preventing ROS formation in a stressed cellular system. HPLC-PDA-MS/MS analysis, revealed a complex polyphenolic fraction. Among the tested pure compounds, 1,5-dicaffeoylquinic acid, apigenin and rutin displayed good α-glucosidase inhibitory activity. Our study suggested new potential of P. casabonae encouraging us to further testing the possible therapeutic potential of this extract

Binge-like administration of alcohol mixed to energy drinks to male adolescent rats severely impacts on mesocortical dopaminergic function in adulthood: A behavioral, neurochemical and electrophysiological study

A growing body of evidence indicates that the practice of consuming alcohol mixed with energy drinks (ED) (AMED) in a binge drinking pattern is significantly diffusing among the adolescent population. This behavior, aimed at increasing the intake of alcohol, raises serious concerns about its long-term effects. Epidemiological studies suggest that AMED consumption might increase vulnerability to alcohol abuse and have a gating effect on the use of illicit drugs. The medial prefrontal cortex (mPFC) is involved in the modulation of the reinforcing effects of alcohol and of impulsive behavior and plays a key role in the development of addiction. In our study, we used a binge-like protocol of administration of alcohol, ED, or AMED in male adolescent rats, to mimic the binge-like intake behavior observed in humans, in order to evaluate whether these treatments could differentially affect the function of mesocortical dopaminergic neurons in adulthood. We did so by measuring: i) physiological sensorimotor gating; ii) voluntary alcohol consumption and dopamine transmission before, during, and after presentation of alcohol; iii) electrophysiological activity of VTA dopaminergic neurons and their sensitivity to a challenge with alcohol. Our results indicate that exposure to alcohol, ED, or AMED during adolescence induces differential adaptive changes in the function of mesocortical dopaminergic neurons and, in particular, that AMED exposure decreases their sensitivity to external stimuli, possibly laying the foundation for the altered behaviors observed in adulthood

Crizotinib in MET-Deregulated or ROS1-Rearranged Pretreated Non-Small Cell Lung Cancer (METROS): A Phase II, Prospective, Multicenter, Two-Arms Trial.

PURPOSE: MET-deregulated NSCLC represents an urgent clinical need because of unfavorable prognosis and lack of specific therapies. Although recent studies have suggested a potential role for crizotinib in patients harboring MET amplification or exon 14 mutations, no conclusive data are currently available. This study aimed at investigating activity of crizotinib in patients harboring MET or ROS1 alterations. PATIENTS AND METHODS: Patients with pretreated advanced NSCLC and evidence of ROS1 rearrangements (cohort A) or MET deregulation (amplification, ratio MET/CEP7 >2.2 or MET exon 14 mutations, cohort B) were treated with crizotinib 250 mg twice daily orally. The coprimary endpoint was objective response rate in the two cohorts. RESULTS: From December 2014 to March 2017, 505 patients were screened and a total of 52 patients (26 patients per cohort) were enrolled onto the study. At data cutoff of September 2017, in cohort A, objective response rate was 65%, and median progression-free survival and overall survival were 22.8 months [95% confidence interval (CI) 15.2-30.3] and not reached, respectively. In cohort B, objective response rate was 27%, median progression-free survival was 4.4 months (95% CI 3.0-5.8), and overall survival was 5.4 months (95% CI, 4.2-6.5). No difference in any clinical endpoint was observed between MET-amplified and exon 14-mutated patients. No response was observed among the 5 patients with cooccurrence of a second gene alteration. No unexpected toxicity was observed in both cohorts. CONCLUSIONS: Crizotinib induces response in a fraction of MET-deregulated NSCLC. Additional studies and innovative therapies are urgently needed