DNA-binding protects p53 from interactions with cofactors involved in transcription-independent functions

Binding-induced conformational changes of a protein at regions distant from the binding site may play crucial roles in protein function and regulation. The p53 tumour suppressor is an example of such an allosterically regulated protein. Little is known, however, about how DNA binding can affect distal sites for transcription factors. Furthermore, the molecular details of how a local perturbation is transmitted through a protein structure are generally elusive and occur on timescales hard to explore by simulations. Thus, we employed state-of-the-art enhanced sampling atomistic simulations to unveil DNA-induced effects on p53 structure and dynamics that modulate the recruitment of cofactors and the impact of phosphorylation at Ser215. We show that DNA interaction promotes a conformational change in a region 3 nm away from the DNA binding site. Specifically, binding to DNA increases the population of an occluded minor state at this distal site by more than 4-fold, whereas phosphorylation traps the protein in its major state. In the minor conformation, the interface of p53 that binds biological partners related to p53 transcription-independent functions is not accessible. Significantly, our study reveals a mechanism of DNA-mediated protection of p53 from interactions with partners involved in the p53 transcription-independent signalling. This also suggests that conformational dynamics is tightly related to p53 signalling

The deep-sea hub of the ANTARES neutrino telescope

The ANTARES neutrino telescope, currently under construction at 2500 m depth off the French Mediterranean coast, will contain 12 detection lines, powered and read out through a deep-sea junction box (JB) hub. Electrical energy from the shore station is distributed through a transformer with multiple secondary windings and a plugboard with 16 deep sea-mateable electro-optic connectors. Connections are made to the JB outputs using manned or remotely operated submersible vehicles. The triply redundant power management and slow control system is based on two identical AC-powered systems, communicating with the shore through 160 Mb/s fibre G-links and a third battery-powered system using a slower link. We describe the power and slow control systems of the underwater hub

Noto Station Status Report

The Noto VLBI station was fully operational in 2012, and the upgrade projects could be restarted, involving mainly the receiver area. Another important improvement was the activation of the 1 Gbps network

NEMO: A Project for a km3^3 Underwater Detector for Astrophysical Neutrinos in the Mediterranean Sea

The status of the project is described: the activity on long term characterization of water optical and oceanographic parameters at the Capo Passero site candidate for the Mediterranean km$^3$ neutrino telescope; the feasibility study; the physics performances and underwater technology for the km$^3$; the activity on NEMO Phase 1, a technological demonstrator that has been deployed at 2000 m depth 25 km offshore Catania; the realization of an underwater infrastructure at 3500 m depth at the candidate site (NEMO Phase 2).Comment: Proceeding of ISCRA 2006, Erice 20-27 June 200

Measurement of the atmospheric muon flux with the NEMO Phase-1 detector

The NEMO Collaboration installed and operated an underwater detector including prototypes of the critical elements of a possible underwater km3 neutrino telescope: a four-floor tower (called Mini-Tower) and a Junction Box. The detector was developed to test some of the main systems of the km3 detector, including the data transmission, the power distribution, the timing calibration and the acoustic positioning systems as well as to verify the capabilities of a single tridimensional detection structure to reconstruct muon tracks. We present results of the analysis of the data collected with the NEMO Mini-Tower. The position of photomultiplier tubes (PMTs) is determined through the acoustic position system. Signals detected with PMTs are used to reconstruct the tracks of atmospheric muons. The angular distribution of atmospheric muons was measured and results compared with Monte Carlo simulations.Comment: Astrop. Phys., accepte

Swift Heavy Ion Induced Modification Studies of C60 Thin Films

Modification induced by 110 MeV Ni ion irradiated thin film samples of C60 on Si and quartz substrates were studied at various fluences. The pristine and irradiated samples were investigated using Raman spectroscopy, electrical conductivity and optical absorption spectroscopy. The Raman data and band gap measurements indicate that swift ions at low fluences result in formations that involve multiple molecular units like dimer or polymer. High fluence irradiation resulted in sub-molecular formations and amorphous semiconducting carbon, indicating overall damage of the fullerene molecules. These sub-molecular units have been identified with nanocrystalline diamond and nanocrystalline graphite like formations.Comment: 7 pages, 29 references and 9 figures submitted to J. Appl. Phy

Measurement of the atmospheric muon depth intensity relation with the NEMO Phase-2 tower

The results of the analysis of the data collected with the NEMO Phase-2 tower, deployed at 3500 m depth about 80 km off-shore Capo Passero (Italy), are presented. Cherenkov photons detected with the photomultipliers tubes were used to reconstruct the tracks of atmospheric muons. Their zenith-angle distribution was measured and the results compared with Monte Carlo simulations. An evaluation of the systematic effects due to uncertainties on environmental and detector parameters is also included. The associated depth intensity relation was evaluated and compared with previous measurements and theoretical predictions. With the present analysis, the muon depth intensity relation has been measured up to 13 km of water equivalent.Comment: submitted to Astroparticle Physic

The epistatic interaction between the dopamine D3 receptor and dysbindin-1 modulates higher-order cognitive functions in mice and humans

The dopamine D2 and D3 receptors are implicated in schizophrenia and its pharmacological treatments. These receptors undergo intracellular trafficking processes that are modulated by dysbindin-1 (Dys). Indeed, Dys variants alter cognitive responses to antipsychotic drugs through D2-mediated mechanisms. However, the mechanism by which Dys might selectively interfere with the D3 receptor subtype is unknown. Here, we revealed an interaction between functional genetic variants altering Dys and D3. Specifically, both in patients with schizophrenia and in genetically modified mice, concomitant reduction in D3 and Dys functionality was associated with improved executive and working memory abilities. This D3/Dys interaction produced a D2/D3 imbalance favoring increased D2 signaling in the prefrontal cortex (PFC) but not in the striatum. No epistatic effects on the clinical positive and negative syndrome scale (PANSS) scores were evident, while only marginal effects on sensorimotor gating, locomotor functions, and social behavior were observed in mice. This genetic interaction between D3 and Dys suggests the D2/D3 imbalance in the PFC as a target for patient stratification and procognitive treatments in schizophrenia