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Strappazzon F.,IRCCS Fondazione Santa Lucia | Di Rita A.,IRCCS Fondazione Santa Lucia | Di Rita A.,University of Rome Tor Vergata | Cianfanelli V.,Danish Cancer Society | And 8 more authors.
Autophagy | Year: 2016

ABSTRACT: Autophagy and apoptosis are 2 stress-response mechanisms that are closely interconnected. However, the molecular interplays between these 2 pathways remain to be clarified. Here we report that the crucial proautophagic factor AMBRA1 can act as a positive mediator of mitochondrial apoptosis. Indeed, we show that, in a proapoptotic positive feedback loop, the C-terminal part of AMBRA1, generated by CASP/CASPASE cleavage upon apoptosis induction, inhibits the antiapoptotic factor BCL2 by a direct binding through its BH3-like domain. The mitochondrial AMBRA1-BCL2 complex is thus at the crossroad between autophagy and cell death and may represent a novel target in development of therapeutic approaches in clinical diseases. © 2016 The Author(s). Published with license by Taylor & Francis Group, LLC

Gandola E.,University of Rome Tor Vergata | Antonioli M.,University of Rome Tor Vergata | Antonioli M.,National Institute For Infectious Diseases L Spallanzani Irccs | Antonioli M.,Albert Ludwigs University of Freiburg | And 4 more authors.
Journal of Microbiological Methods | Year: 2016

Toxigenic cyanobacteria are one of the main health risks associated with water resources worldwide, as their toxins can affect humans and fauna exposed via drinking water, aquaculture and recreation. Microscopy monitoring of cyanobacteria in water bodies and massive growth systems is a routine operation for cell abundance and growth estimation. Here we present ACQUA (Automated Cyanobacterial Quantification Algorithm), a new fully automated image analysis method designed for filamentous genera in Bright field microscopy. A pre-processing algorithm has been developed to highlight filaments of interest from background signals due to other phytoplankton and dust. A spline-fitting algorithm has been designed to recombine interrupted and crossing filaments in order to perform accurate morphometric analysis and to extract the surface pattern information of highlighted objects. In addition, 17 specific pattern indicators have been developed and used as input data for a machine-learning algorithm dedicated to the recognition between five widespread toxic or potentially toxic filamentous genera in freshwater: Aphanizomenon, Cylindrospermopsis, Dolichospermum, Limnothrix and Planktothrix. The method was validated using freshwater samples from three Italian volcanic lakes comparing automated vs. manual results. ACQUA proved to be a fast and accurate tool to rapidly assess freshwater quality and to characterize cyanobacterial assemblages in aquatic environments. © 2015 Elsevier B.V.

Franzetti M.,University of Milan | Violin M.,University of Milan | Antinori A.,National Institute For Infectious Diseases L Spallanzani Irccs | De Luca A.,University of Siena | And 7 more authors.
BMC Infectious Diseases | Year: 2014

Background: Despite a substantial reduction in virological failures following introduction of new potent antiretroviral therapies in the latest years, drug resistance remains a limitation for the control of HIV-1 infection. We evaluated trends and correlates of resistance in treatment failing patients in a comprehensive database over a time period of relevant changes in prescription attitudes and treatment guidelines.Methods: We analyzed 6,796 HIV-1 pol sequences from 49 centres stored in the Italian ARCA database during the 2003-2012 period. Patients (n = 5,246) with viremia > 200 copies/mL received a genotypic test while on treatment. Mutations were identified from IAS-USA 2013 tables. Class resistance was evaluated according to antiretroviral regimens in use at failure. Time trends and correlates of resistance were analyzed by Cochran-Armitage test and logistic regression models.Results: The use of NRTI backbone regimens slightly decreased from 99.7% in 2003-2004 to 97.4% in 2010-2012. NNRTI-based combinations dropped from 46.7% to 24.1%. PI-containing regimens rose from 56.6% to 81.7%, with an increase of boosted PI from 36.5% to 68.9% overtime. In the same reference periods, Resistance to NRTIs, NNRTIs and PIs declined from 79.1% to 40.8%, from 77.8% to 53.8% and from 59.8% to 18.9%, respectively (p < .0001 for all comparisons). Dual NRTI + NNRTI and NRTI + PI resistance decreased from 56.4% to 33.3% and from 36.1% to 10.5%, respectively. Reduced risk of resistance over time periods was confirmed by a multivariate analysis.Conclusions: Mutations associated with NRTIs, NNRTIs and PIs at treatment failure declined overtime regardless of specific class combinations and epidemiological characteristics of treated population. This is likely due to the improvement of HIV treatment, including both last generation drug combinations and prescription guidelines. © 2014 Franzetti et al.; licensee BioMed Central Ltd.

Prosperi M.C.F.,Catholic University of the Sacred Heart | Cozzi-Lepri A.,University College London | Antinori A.,National Institute For Infectious Diseases L Spallanzani Irccs | Cassola G.,Ospedale Galliera | And 6 more authors.
HIV Medicine | Year: 2011

Background: This study provides an estimate of the proportion of HIV-positive patients in Italian clinics showing an 'adverse prognosis' (defined as a CD4 count ≤200cells/μL or an HIV RNA >50 HIV-1 RNA copies/mL) over time, and investigates whether this proportion varied according to patients' characteristics. Methods: We estimated the annual proportion of patients with a CD4 count ≤200cells/μL or HIV RNA >50copies/mL out of the total number of patients in the Icona Foundation cohort seen in any given year, both overall and after stratifying by demographical and treatment status groups. Generalized estimating equation models for Poisson regression were applied. Results: In 1998-2008, the prevalence of patients with a CD4 count ≤200cells/μL decreased from 14 to 6% [adjusted relative risk (RR) 0.86/year; 95% confidence interval (CI) 0.84-0.88; P<0.0001]. The prevalence of HIV RNA >50copies/mL decreased from 66 to 40% (adjusted RR 0.95/year; 95% CI 0.95-0.96; P<0.0001) in all patients and from 38 to 12% in the subgroup of patients who had previously received antiretroviral therapy (ART) for ≥6 months (adjusted RR 0.89/year; 95% CI 0.88-0.90; P<0.0001). Conclusions: There was a substantial increase in the success rate of ART in Italy in 1998-2008, resulting in a lower percentage of patients with adverse prognosis in recent years. The use of ART seemed to be the most important determinant of viral load outcome, regardless of mode of transmission. Although injecting drug users showed a less marked improvement in CD4 cell count over time than other risk groups, they showed a similar improvement in detectable viral load. © 2010 British HIV Association.

Antonioli M.,National Institute For Infectious Diseases L Spallanzani Irccs | Antonioli M.,University of Rome Tor Vergata | Albiero F.,National Institute For Infectious Diseases L Spallanzani Irccs | Albiero F.,University of Rome Tor Vergata | And 18 more authors.
Developmental Cell | Year: 2014

Autophagy maintains cellular homeostasis by degrading harmful or unnecessary intracellular components. How the autophagy response is induced rapidly and transiently remains largely unknown. We report that the E3 ubiquitin ligases Cullin-5 and Cullin-4 regulate the onset and termination of autophagy, respectively, by dynamically interacting with AMBRA1, a regulator of autophagy. Under normal conditions, Cullin-4 binding to AMBRA1 limits its protein abundance. Autophagy stimuli promote AMBRA1 stabilization by causing ULK1-dependent Cullin-4 release. Notably, Cullin-4/AMBRA1 dissociation is transient, and the re-established interaction triggers AMBRA1 degradation, terminating the autophagy response. Moreover, Cullin-4 inhibits the interaction between AMBRA1 and another Cullin E3 ligase. Indeed, upon Cullin-4 dissociation, AMBRA1 binds and inhibits Cullin-5, thus promoting the accumulation of the mTOR inhibitor DEPTOR. Through DEPTOR stabilization, AMBRA1 establishes a feedback loop that ensures the rapid onset of autophagy by enhancing mTOR inactivation. Our findings show that Cullin-mediated degradation of autophagy regulators temporally controls the autophagy response. © 2014 Elsevier Inc.

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