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D'Angelo P.,University of Rome La Sapienza | Della Longa S.,University of L'Aquila | Arcovito A.,Catholic University of the Sacred Heart | Mancini G.,CASPUR | And 9 more authors.
Biochemistry | Year: 2012

Prion diseases are a class of fatal neurodegenerative disorders characterized by brain spongiosis, synaptic degeneration, microglia and astrocytes activation, neuronal loss and altered redox control. These maladies can be sporadic, iatrogenic and genetic. The etiological agent is the prion, a misfolded form of the cellular prion protein, PrPC. PrPC interacts with metal ions, in particular copper and zinc, through the octarepeat and non-octarepeat binding sites. The physiological implication of this interaction is still unclear, as is the role of metals in the conversion. Since prion diseases present metal dyshomeostasis and increased oxidative stress, we described the copper-binding site located in the human C-terminal domain of PrP-HuPrP(90-231), both in the wild-type protein and in the protein carrying the pathological mutation Q212P. We used the synchrotron-based X-ray absorption fine structure technique to study the Cu(II) and Cu(I) coordination geometries in the mutant, and we compared them with those obtained using the wild-type protein. By analyzing the extended X-ray absorption fine structure and the X-ray absorption near-edge structure, we highlighted changes in copper coordination induced by the point mutation Q212P in both oxidation states. While in the wild-type protein the copper-binding site has the same structure for both Cu(II) and Cu(I), in the mutant the coordination site changes drastically from the oxidized to the reduced form of the copper ion. Copper-binding sites in the mutant resemble those obtained using peptides, confirming the loss of short- and long-range interactions. These changes probably cause alterations in copper homeostasis and, consequently, in redox control. © 2012 American Chemical Society.

Beraldin J.A.,National Research Council Canada | Picard M.,National Research Council Canada | Bandiera A.,University of Salento | Valzano V.,University of Salento | Negro F.,CASPUR
Proceedings of SPIE - The International Society for Optical Engineering | Year: 2011

The Grotta dei Cervi is a Neolithic cave where human presence has left many unique pictographs on the walls of many of its chambers. It was closed for conservation reasons soon after its discovery in 1970. It is for these reasons that a 3D documentation was started. Two sets of high resolution and detailed three-dimensional (3D) acquisitions were captured in 2005 and 2009 respectively, along with two-dimensional (2D) images. From this information a textured 3D model was produced for most of the 300-m long central corridor. Carbon dating of the guano used for the pictographs and environmental monitoring (Temperature, Relative humidity, and Radon) completed the project. This paper presents this project, some results obtained up to now, the best practice that has emerged from this work and a description of the processing pipeline that deals with more than 27 billion 3D coordinates. © 2011 SPIE-IS&T.

Cecchi R.,University of Rome La Sapienza | Sestili C.,University of Rome La Sapienza | Prosperini G.,CASPUR | Cecchetto G.,University of Padua | And 3 more authors.
International Journal of Legal Medicine | Year: 2014

Forensic pathologists are often asked to provide evidence of asphyxia death in the trial and a histological marker of asphyxiation would be of great help. Data from the literature indicate that the reaction of lung tissue cells to asphyxia may be of more interest for forensic purposes than migrating cells. The lungs of 62 medico-legal autopsy cases, 34 acute mechanical asphyxia (AMA), and 28 control cases (CC), were immunostained with anti-P-selectin, anti-E-selectin, anti-SP-A, and anti-HIF1-α antibodies, in order to verify if some of them may be used as markers of asphyxia death. Results show that P- and E-selectins expression in lung vessels, being activated by several types of trigger stimuli not specific to hypoxia, cannot be used as indicator of asphyxia. Intra-alveolar granular deposits of SP-A seem to be related to an intense hypoxic stimulus, and when massively present, they can suggest, together with other elements, a severe hypoxia as the mechanism of death. HIF1-α was expressed in small-, medium-, and large-caliber lung vessels of the vast majority of mechanical asphyxia deaths and CO intoxications, with the number and intensity of positive-stained vessels increasing with the duration of the hypoxia. Although further confirmation studies are required, these preliminary data indicate an interesting potential utility of HIF1-α as a screening test for asphyxia deaths. © 2013 Springer-Verlag Berlin Heidelberg.

Tiribocchi A.,University of Bari | Gonnella G.,University of Bari | Marenduzzo D.,University of Edinburgh | Orlandini E.,University of Padua | Salvadore F.,Caspur
Physical Review Letters | Year: 2011

Blue phases are liquid crystals made up by networks of defects, or disclination lines. While existing phase diagrams show a striking variety of competing metastable topologies for these networks, very little is known as to how to kinetically reach a target structure, or how to switch from one to the other, which is of paramount importance for devices. We theoretically identify two confined blue phase I systems in which by applying an appropriate series of electric field it is possible to select one of two bistable defect patterns. Our results may be used to realize new generation and fast switching energy-saving bistable devices in ultrathin surface treated blue phase I wafers. © 2011 American Physical Society.

Melchionna S.,CNR Institute for Chemical and Physical Processes | Amati G.,CASPUR | Bernaschi M.,CNR Institute for applied mathematics Mauro Picone | Bisson M.,CNR Institute for applied mathematics Mauro Picone | And 3 more authors.
Medical Engineering and Physics | Year: 2013

We present the results of a computational study of the entire left coronary system simulated both at Newtonian level and at red blood cell resolution for a sizeable number of physiological conditions. We analyze the cardiovascular implications of stenotic plaques and show that the standard clinical criterion for surgical or percutaneous intervention, based on the fractional flow reserve (FFR), is significantly affected by system-dependent, local hemodynamic factors. A refined version, based on the new notion of local FFR response to stenotic growth, and accounting for statistical uncertainties due to flow heterogeneity, is suggested and illustrated. © 2013 IPEM.

Marinello J.,University of Bologna | Chillemi G.,CASPUR | Bueno S.,CASPUR | Manzo S.G.,University of Bologna | Capranico G.,University of Bologna
Nucleic Acids Research | Year: 2013

DNA Topoisomerase I (Top1) is required to relax DNA supercoils generated by RNA polymerases (RNAPs). Top1 is inhibited with high specificity by camptothecin (CPT), an effective anticancer agent, and by oxidative base damage and ribonucleotides in DNA strands, resulting into Top1-DNA cleavage complexes (Top1ccs). To understand how Top1ccs affect genome stability, we have investigated the global transcriptional response to CPT-induced Top1ccs. Top1ccs trigger an accumulation of antisense RNAPII transcripts specifically at active divergent CpG-island promoters in a replication-independent and Top1-dependent manner. As CPT increases antisense transcript levels in the presence of 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole, a transcription inhibitor, Top1ccs likely impair antisense RNA degradation. Time-course data showed a burst of Top1ccs increased by CPT at promoter sites and along transcribed regions, causing a transient block of RNAPII at the promoter. Moreover, cell immunofluorescence analyses showed that Top1ccs induce a transient increase of R-loops specifically at highly transcribed regions such as nucleoli in a Top1-dependent manner. Thus, a specific and highly dynamic transcriptional response to Top1ccs occurs at divergent active CpG-island promoters, which may include a transient stabilization of R-loops. The results clarify molecular features of a response pathway leading to transcription-dependent genome instability and altered transcription regulation. © 2013 The Author(s).

Salvadore F.,CASPUR | Bernardini M.,University of Rome La Sapienza | Botti M.,CASPUR
Journal of Computational Physics | Year: 2013

Graphical processing units (GPUs), characterized by significant computing performance, are nowadays very appealing for the solution of computationally demanding tasks in a wide variety of scientific applications. However, to run on GPUs, existing codes need to be ported and optimized, a procedure which is not yet standardized and may require non trivial efforts, even to high-performance computing specialists. In the present paper we accurately describe the porting to CUDA (Compute Unified Device Architecture) of a finite-difference compressible Navier-Stokes solver, suitable for direct numerical simulation (DNS) of turbulent flows. Porting and validation processes are illustrated in detail, with emphasis on computational strategies and techniques that can be applied to overcome typical bottlenecks arising from the porting of common computational fluid dynamics solvers. We demonstrate that a careful optimization work is crucial to get the highest performance from GPU accelerators. The results show that the overall speedup of one NVIDIA Tesla S2070 GPU is approximately 22 compared with one AMD Opteron 2352 Barcelona chip and 11 compared with one Intel Xeon X5650 Westmere core. The potential of GPU devices in the simulation of unsteady three-dimensional turbulent flows is proved by performing a DNS of a spatially evolving compressible mixing layer. © 2012 Elsevier Inc.

Mancini G.,CASPUR | D'Annessa I.,CASPUR | D'Annessa I.,University of Rome Tor Vergata | Coletta A.,University of Rome Tor Vergata | And 3 more authors.
PLoS ONE | Year: 2010

Background: Human topoisomerase I catalyzes the relaxation of DNA supercoils in fundamental cell processes like transcription, replication and chromosomal segregation. It is the only target of the camptothecin family of anticancer drugs. Among these, topotecan has been used to treat lung and ovarian carcinoma for several years. Camptothecins reversibly binds to the covalent intermediate DNA-enzyme, stabilizing the cleavable complex and reducing the religation rate. The stalled complex then collides with the progression of the replication fork, producing lethal double strand DNA breaks and eventually cell death. Methodology/Principal Findings: Long lasting molecular dynamics simulations of the DNA-topoisomerase I binary complex and of the DNA-topoisomerase-topotecan ternary complex have been performed and compared. The conformational space sampled by the binary complex is reduced by the presence of the drug, as observed by principal component and cluster analyses. This conformational restraint is mainly due to the reduced flexibility of residues 633-643 (the region connecting the linker to the core domain) that causes an overall mobility loss in the ternary complex linker domain. During the simulation, DNA/drug stacking interactions are fully maintained, and hydrogen bonds are maintained with the enzyme. Topotecan keeps the catalytic residue Lys532 far from the DNA, making it unable to participate to the religation reaction. Arg364 is observed to interact with both the B and E rings of topotecan with two stable direct hydrogen bonds. An interesting constrain exerted by the protein on the geometrical arrangement of topotecan is also observed. Conclusions/Significance: Atomistic-scale understanding of topotecan interactions with the DNA-enzyme complex is fundamental to the explaining of its poisonous effect and of the drug resistance observed in several single residue topoisomerase mutants. We observed significant alterations due to topotecan in both short-range interactions and longrange protein domain communications. © 2010 Mancini et al.

Salvadore F.,CASPUR
Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) | Year: 2012

Cube-Flu is a Python software application that produces Fortran code for solving Partial Differential Equations (PDEs), according to the input provided by the user. The code produced by Cube-Flu is designed for exploiting distribuited memory architectures as well as Graphics Processing Units, as shown in the next section. The software solves equations of the form on cartesian grids, using Runge-Kutta time integration, and finite difference schemes. The idea behind the application is to provide a simple framework for solving a wide class of systems of equations, using a natural and intuitive syntax. © 2012 Springer-Verlag.

D'Angelo P.,University of Rome La Sapienza | Della Longa S.,University of L'Aquila | Arcovito A.,Catholic University of the Sacred Heart | Anselmi M.,University of Rome La Sapienza | And 2 more authors.
Journal of the American Chemical Society | Year: 2010

The effect of structural disorder on the X-ray absorption near-edge structure (XANES) spectrum of a heme protein has been investigated using the dynamical description of the system derived from molecular dynamics (MD) simulations. The XANES spectra of neuroglobin (Ngb) and carbonmonoxy-neuroglobin (NgbCO) have been quantitatively reproduced, starting from the MD geometrical configurations, without carrying out any optimization in the structural parameter space. These results provide an important experimental validation of the reliability of the potentials used in the MD simulations and accordingly corroborate the consistency of the structural dynamic information on the metal center, related to its biological function. This analysis allowed us to demonstrate that the configurational disorder associated with the distortion of the heme plane and with the different orientations of the axial ligands can affect the XANES features at very low energy. Neglecting configurational disorder in the XANES quantitative analysis of heme proteins is a source of systematic errors in the determination of Fe coordination geometry. The combined use of XANES and MD is a novel strategy to enhance the resolution and reliability of the structural information obtained on metalloproteins, making the combination of these techniques powerful for metalloprotein investigations. © 2010 American Chemical Society.

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