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MicroRNA-1 Downregulation Increases Connexin 43 Displacement and Induces Ventricular Tachyarrhythmias in Rodent Hypertrophic Hearts
Antonio Curcio, Daniele Torella, Claudio Iaconetti, Eugenia Pasceri, Jolanda Sabatino, Sabato Sorrentino, Salvatore Giampà, Mariella Micieli, Alberto Polimeni, Beverley J. Henning, Angelo Leone, Daniele Catalucci, Georgina M. Ellison, Gianluigi Condorelli, Ciro Indolfi
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0070158
Abstract: Downregulation of the muscle-specific microRNA-1 (miR-1) mediates the induction of pathologic cardiac hypertrophy. Dysfunction of the gap junction protein connexin 43 (Cx43), an established miR-1 target, during cardiac hypertrophy leads to ventricular tachyarrhythmias (VT). However, it is still unknown whether miR-1 and Cx43 are interconnected in the pro-arrhythmic context of hypertrophy. Thus, in this study we investigated whether a reduction in the extent of cardiac hypertrophy could limit the pathological electrical remodeling of Cx43 and the onset of VT by modulating miR-1 levels. Wistar male rats underwent mechanical constriction of the ascending aorta to induce pathologic left ventricular hypertrophy (LVH) and afterwards were randomly assigned to receive 10mg/kg valsartan, VAL (LVH+VAL) delivered in the drinking water or placebo (LVH) for 12 weeks. Sham surgery was performed for control groups. Programmed ventricular stimulation reproducibly induced VT in LVH compared to LVH+VAL group. When compared to sham controls, rats from LVH group showed a significant decrease of miR-1 and an increase of Cx43 expression and its ERK1/2-dependent phosphorylation, which displaces Cx43 from the gap junction. Interestingly, VAL administration to rats with aortic banding significantly reduced cardiac hypertrophy and prevented miR-1 down-regulation and Cx43 up-regulation and phosphorylation. Gain- and loss-of-function experiments in neonatal cardiomyocytes (NCMs) in vitro confirmed that Cx43 is a direct target of miR-1. Accordingly, in vitro angiotensin II stimulation reduced miR-1 levels and increased Cx43 expression and phosphorylation compared to un-stimulated NCMs. Finally, in vivo miR-1 cardiac overexpression by an adenoviral vector intra-myocardial injection reduced Cx43 expression and phosphorylation in mice with isoproterenol-induced LVH. In conclusion, miR-1 regulates Cx43 expression and activity in hypertrophic cardiomyocytes in vitro and in vivo. Treatment of pressure overload-induced myocyte hypertrophy reduces the risk of life-threatening VT by normalizing miR-1 expression levels with the consequent stabilization of Cx43 expression and activity within the gap junction.
Optimal Drug Synergy in Antimicrobial Treatments
Joseph Peter Torella,Remy Chait,Roy Kishony
PLOS Computational Biology , 2010, DOI: 10.1371/journal.pcbi.1000796
Abstract: The rapid proliferation of antibiotic-resistant pathogens has spurred the use of drug combinations to maintain clinical efficacy and combat the evolution of resistance. Drug pairs can interact synergistically or antagonistically, yielding inhibitory effects larger or smaller than expected from the drugs' individual potencies. Clinical strategies often favor synergistic interactions because they maximize the rate at which the infection is cleared from an individual, but it is unclear how such interactions affect the evolution of multi-drug resistance. We used a mathematical model of in vivo infection dynamics to determine the optimal treatment strategy for preventing the evolution of multi-drug resistance. We found that synergy has two conflicting effects: it clears the infection faster and thereby decreases the time during which resistant mutants can arise, but increases the selective advantage of these mutants over wild-type cells. When competition for resources is weak, the former effect is dominant and greater synergy more effectively prevents multi-drug resistance. However, under conditions of strong resource competition, a tradeoff emerges in which greater synergy increases the rate of infection clearance, but also increases the risk of multi-drug resistance. This tradeoff breaks down at a critical level of drug interaction, above which greater synergy has no effect on infection clearance, but still increases the risk of multi-drug resistance. These results suggest that the optimal strategy for suppressing multi-drug resistance is not always to maximize synergy, and that in some cases drug antagonism, despite its weaker efficacy, may better suppress the evolution of multi-drug resistance.
Investigating dynamic and energetic determinants of protein nucleic acid recognition: analysis of the zinc finger zif268-DNA complexes
Rubben Torella, Elisabetta Moroni, Michele Caselle, Giulia Morra, Giorgio Colombo
BMC Structural Biology , 2010, DOI: 10.1186/1472-6807-10-42
Abstract: To this aim, we apply novel theoretical approaches to analyze the dynamics and energetics of biological systems starting from MD trajectories. As model system, we chose different sequences of Zinc Fingers (ZF) of the Zif268 family bound with different sequences of DNA. The complexes differ for their experimental stability properties, but share the same overall 3 D structure and do not undergo structural modifications during the simulations. The results of our analysis suggest that the energy landscape for DNA binding may be populated by dynamically different states, even in the absence of major conformational changes. Energetic couplings between residues change in response to protein and/or DNA sequence variations thus modulating the selectivity of recognition and the relative importance of different regions for binding.The results show differences in the organization of the intra-protein energy-networks responsible for the stabilization of the protein conformations recognizing and binding DNA. These, in turn, are reflected into different modulation of the ZF's internal dynamics. The results also show a correlation between energetic and dynamic properties of the different proteins and their specificity/selectivity for DNA sequences. Finally, a dynamic and energetic model for the recognition of DNA by Zinc Fingers is proposed.Protein-DNA recognition mechanisms underlie the functioning and regulation of several cellular processes ranging from transcription to replication, modification and restriction. Consequently, it is not surprising that questions on how to achieve a detailed molecular understanding of these phenomena have emerged since the first X-ray structures of complexes appeared.One of the central problems involves the understanding of how a certain binding protein efficiently selects a specific target sequence from a large number of possible sites [1]. Initial studies concentrated on the specific hydrogen bonding between aminoacid side-chains and DNA bases [
Ten Years of the Central Italy Electromagnetic Network (CIEN) Continuous Monitoring  [PDF]
Cristiano Fidani, Daniele Marcelli
Open Journal of Earthquake Research (OJER) , 2017, DOI: 10.4236/ojer.2017.62004
Abstract: A test is being realised by means of a network of wide band electromagnetic detectors that continuously records the electric components of the electromagnetic field, ranging from a few of Hz to tens of kHz. The network has been operating in central Italy for more than ten years. The recorded signals from this network have been analysed in real time as well as their power spectrum contents. Time/frequency data have been saved for further analysis. The spectral contents have evidenced very distinct power spectrum signatures in ELF band that increase in intensity when strong seismic activity occurs near the stations, for example, at the time of Amatrice (M = 6) and Norcia (M = 6.5) earthquakes in 2016 when ten stations were operative, at the time of the Emilia (M = 6) earthquakes in 2012 when nine stations were operative, and at the time of the L’Aquila (M = 6.3) earthquakes in 2009 when only two stations were operative. Strong signals were also detected during the moderate Ancona (M = 5) earthquake in 2013 and by the recently installed Avigliano Umbro, Città di Castello and Gubbio stations in the Umbria region, during small seismic swarms (2 < M < 4) between 2013 and 2014. CIEN is presently composed of 16 stations and collect data from a multidisciplinary instrumentation.
Monitoring and Identification of the Seismically Isolated “Our Lady of Tears” Shrine in Syracuse  [PDF]
Daniele Losanno, Mariacristina Spizzuoco
Open Journal of Civil Engineering (OJCE) , 2018, DOI: 10.4236/ojce.2018.84028
Abstract: This paper describes the installation and management of the monitoring system of the “Our Lady of Tears Shrine” in Syracuse, whose dome is an imposing r.c. and prestressed r.c. structure of about 22,000 ton that was seismically isolated by flat sliding devices with hysteretic dampers. The monitoring system, representing an upgrading and improvement of an old system never made working, has some innovative features, because it allows to manage with the same dedicated hardware and software both the slow (thermal variations, relative humidity, wind direction and velocity) and the fast acquisitions (dynamic vibrations by wind and earthquake). The monitoring system was inserted among those structures maintained and controlled by the Seismic Observatory of Structures of the National Department of Civil Protection. Some records of low magnitude earthquakes allowed to validate the correct behaviour of the whole structure, as well as to make a dynamic identification of the complex construction and to calibrate a detailed finite element model of the Sanctuary, thus predicting isolators’ behaviour under design earthquake.
Self gravitating cosmic strings and the Alexandrov's inequality for Liouville-type equations
Daniele Bartolucci,Daniele Castorina
Mathematics , 2014,
Abstract: Motivated by the study of self gravitating cosmic strings, we pursue the well known method by C. Bandle to obtain a weak version of the classical Alexandrov's isoperimetric inequality. In fact we derive some quantitative estimates for weak subsolutions of a Liouville-type equation with conical singularities. Actually we succeed in generalizing previously known results, including Bol's inequality and pointwise estimates, to the case where the solutions solve the equation just in the sense of distributions. Next, we derive some \uv{new} pointwise estimates suitable to be applied to a class of singular cosmic string equations. Finally, interestingly enough, we apply these results to establish a minimal mass property for solutions of the cosmic string equation which are \uv{supersolutions} of the singular Liouville-type equation.
A global existence result for a Keller-Segel type system with supercritical initial data
Daniele Bartolucci,Daniele Castorina
Mathematics , 2015,
Abstract: We consider a parabolic-elliptic Keller-Segel type system, which is related to a simplified model of chemotaxis. Concerning the maximal range of existence of solutions, there are essentially two kinds of results: either global existence in time for general subcritical ($\|\rho_0\|_1<8\pi$) initial data, or blow--up in finite time for suitably chosen supercritical ($\|\rho_0\|_1>8\pi$) initial data with concentration around finitely many points. As a matter of fact there are no results claiming the existence of global solutions in the supercritical case. We solve this problem here and prove that, for a particular set of initial data which share large supercritical masses, the corresponding solution is global and uniformly bounded.
T7 RNA Polymerase Functions In Vitro without Clustering
Kieran Finan, Joseph P. Torella, Achillefs N. Kapanidis, Peter R. Cook
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0040207
Abstract: Many nucleic acid polymerases function in clusters known as factories. We investigate whether the RNA polymerase (RNAP) of phage T7 also clusters when active. Using ‘pulldowns’ and fluorescence correlation spectroscopy we find that elongation complexes do not interact in vitro with a Kd<1 μM. Chromosome conformation capture also reveals that genes located 100 kb apart on the E. coli chromosome do not associate more frequently when transcribed by T7 RNAP. We conclude that if clustering does occur in vivo, it must be driven by weak interactions, or mediated by a phage-encoded protein.
Assessment of debris flow magnitude in small catchments of the lombardy alps: the val gola case study  [PDF]
Daniele de Wrachien, Stefano Mambretti
Agricultural Sciences (AS) , 2011, DOI: 10.4236/as.2011.21002
Abstract: Debris flows are among the most destructive of all water-related disasters. They mainly affect mountain areas in a wide range of morpho- climatic environments. Therefore, accurate pre-diction of their run out distances, magnitudes and velocities plays a role of paramount impor-tance, in order to plan and design appropriate structural and non-structural defence measures. In this context, a number of Authors have de-veloped methods feasible to evaluate the ten-dency of a catchment to generate debris flow, without giving an estimation of the magnitude. Other empirical procedures are based on the analysis of historical series of debris flow, oc-curred in similar environments, to assess the relationship between the catchment character-istics and the maximum movable debris vol-umes. In this paper, and with reference to Val Gola—a small catchment in the North-East Lom- bardy where debris flows frequently occur—a number of methods, belonging to each of the above mentioned categories, have been briefly reviewed and applied in order to evaluate their effectiveness and consistency.
Challenges and Constraints in Irrigation and Drainage Development: A World-Wide View  [PDF]
Marco Medici, Daniele De Wrachien
Voice of the Publisher (VP) , 2016, DOI: 10.4236/vp.2016.22002
Abstract: In order to increase food production it is necessary to better understand all the factors underlying short term operations and long term strategies that lead to improve food security. In this regard any good effect deriving from agricultural research is strictly connected to a more accurate estimation of crops resources requirements, to major improvements in the use of irrigation and drainage systems, to a better understand of climatic variability. All the variables involved show strong dependency on both place and time. The failing of past, present and future systems can be essentially attributed to poor agricultural research planning, to incorrect agricultural systems design and resource allocation and to a not complete capacity to cope with short and long-term global climatic behavior.
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