Application of ALPIDE pixel detector for heavy-ion nuclear experiment and ion therapy

International audienceWe present computer simulation data for the dielectric constant of a system of uniform polarizable spheres randomly distributed in a homogeneous background. The deviations from the Clausius-Mossotti formula are found for seven values of the volume fraction. In addition, the spectral density which appears in the Bergman representation of the dielectric constant is determined. The spectrum obtained with a sufficient number of higher-order multipoles differs significantly from that found with just dipolar or dipole-quadrupolar interactions

Mitochondrial ROS control neuronal excitability and cell fate in frontotemporal dementia.

INTRODUCTION: The second most common form of early-onset dementia-frontotemporal dementia (FTD)-is often characterized by the aggregation of the microtubule-associated protein tau. Here we studied the mechanism of tau-induced neuronal dysfunction in neurons with the FTD-related 10+16 MAPT mutation. METHODS: Live imaging, electrophysiology, and redox proteomics were used in 10+16 induced pluripotent stem cell-derived neurons and a model of tau spreading in primary cultures. RESULTS: Overproduction of mitochondrial reactive oxygen species (ROS) in 10+16 neurons alters the trafficking of specific glutamate receptor subunits via redox regulation. Increased surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors containing GluA1 and NR2B subunits leads to impaired glutamatergic signaling, calcium overload, and excitotoxicity. Mitochondrial antioxidants restore the altered response and prevent neuronal death. Importantly, extracellular 4R tau induces the same pathological response in healthy neurons, thus proposing a mechanism for disease propagation. DISCUSSION: These results demonstrate mitochondrial ROS modulate glutamatergic signaling in FTD, and suggest a new therapeutic strategy

Physical study of proton therapy at CANAM laboratory on medulloblastoma cell lines DAOY

2.0 MeV proton beam accelerated at Tandetron is extracted in air through a thin film and allowed to scatter to irradiate the cell culture attached to the polymeric base of a biological flask. The irradiated cells were human medulloblastoma cell line Daoy treated with and without 5 nm sized spherical gold nanoparticles. Proton doses from 0.5 to 1.5 Gy have been employed to irradiate the cultures and to investigate the role of the radiotherapy performed with and without the use of the gold nanoparticles. Results indicated that cell survival is significantly reduced to about 50% when the nanoparticles at a concentration of about 6 × 1013 particles/ml are employed

Clustered DNA damage on subcellular level: effect of scavengers

Clustered DNA damages are induced by ionizing radiation, particularly of high linear energy transfer (LET). Compared to isolated DNA damage sites, their biological effects can be more severe. We investigated a clustered DNA damage induced by high LET radiation (C 290 MeV u(-1) and Fe 500 MeV u(-1)) in pBR322 plasmid DNA. The plasmid is dissolved in pure water or in aqueous solution of one of the three scavengers (coumarin-3-carboxylic acid, dimethylsulfoxide, and glycylglycine). The yield of double strand breaks (DSB) induced in the DNA plasmid-scavenger system by heavy ion radiation was found to decrease with increasing scavenging capacity due to reaction with hydroxyl radical, linearly with high correlation coefficients. The yield of non-DSB clusters was found to occur twice as much as the DSB. Their decrease with increasing scavenging capacity had lower linear correlation coefficients. This indicates that the yield of non-DSB clusters depends on more factors, which are likely connected to the chemical properties of individual scavengers

Radiation-induced oxidation of proteins in DNA-protein complexes.

A key step in the regulation of gene expression, DNA structuring and DNA repair is the binding of some proteins to specific DNA sequences. Previously we have shown that DNA-binding proteins are acting as efficient protectors against the attack of hydroxyl radicals produced by water radiolysis. They protect their binding sites on DNA by shielding and by radicals scavenging. They also modify the conformation of DNA (compaction, bending) thereby rendering DNA more resistant to radiolysis. But proteins are also vulnerable and get damaged under irradiation. The progressive accumulation of damages on the protein (mainly side chain modifications) firstly affects the configuration of the DNA-protein couple and finally renders the protein unable to play its protective role: the protein loses its ability to bind to its specific DNA sequence. We have studied the effect of irradiation on the E. coli lactose operator-repressor complex. At low doses the protein protects its specific binding site on DNA. At high doses, the complex is disrupted mainly due to the damage to the protein. CD data show that upon irradiation, the structure and the stability of the binding domain of the protein (the headpiece) changes. Fluorescence measurements reveal the degradation of tyrosine residues. Mass spectrometry data complemented by RADACK calculations allow identifying all the oxidized amino-acids of the DNA binding domains of the proteins. Molecular dynamics simulations reveal and characterize the structural changes induced by the oxidation of each amino-acid in the headpiece. Most of the identified oxidized amino-acids are essential for the DNA-protein interaction as revealed by the analysis of the NMR- or crystallography-based structures of the complexes. Thus, irradiation can critically affect proteins properties and consequently can hinder their binding to DNA, due to the oxidation of amino-acids of the DNA-binding domain and to the subsequent conformational changes of it

CONTRIBUTION OF INDIRECT EFFECTS TO CLUSTERED DAMAGE IN DNA IRRADIATED WITH PROTONS

Protons are the dominant particles both in galactic cosmic rays and in solar particle events and, furthermore, proton irradiation becomes increasingly used in tumour treatment. It is believed that complex DNA damage is the determining factor for the consequent cellular response to radiation. DNA plasmid pBR322 was irradiated at U120-M cyclotron with 30 MeV protons and treated with two Escherichia coli base excision repair enzymes. The yields of SSBs and DSBs were analysed using agarose gel electrophoresis. DNA has been irradiated in the presence of hydroxyl radical scavenger (coumarin-3-carboxylic acid) in order to distinguish between direct and indirect damage of the biological target. Pure scavenger solution was used as a probe for measurement of induced OH center dot radical yields. Experimental OH center dot radical yield kinetics was compared with predictions computed by two theoretical models-RADAMOL and Geant4-DNA. Both approaches use Geant4-DNA for description of physical stages of radiation action, and then each of them applies a distinct model for description of the pre-chemical and chemical stage

Radiationinduced oxidation of proteins in DNA-protein complexes

International audienceA key step in the regulation of gene expression, DNA structuring and DNA repair is the binding of some proteins to specific DNA sequences. Previously we have shown that DNA-binding proteins are acting as efficient protectors against the attack of hydroxyl radicals produced by water radiolysis. They protect their binding sites on DNA by shielding and by radicals scavenging. They also modify the conformation of DNA (compaction, bending) thereby rendering DNA more resistant to radiolysis. But proteins are also vulnerable and get damaged under irradiation. The progressive accumulation of damages on the protein (mainly side chain modifications) firstly affects the configuration of the DNA-protein couple and finally renders the protein unable to play its protective role: the protein loses its ability to bind to its specific DNA sequence. We have studied the effect of irradiation on the E. coli lactose operator-repressor complex. At low doses the protein protects its specific binding site on DNA. At high doses, the complex is disrupted mainly due to the damage to the protein. CD data show that upon irradiation, the structure and the stability of the binding domain of the protein (the headpiece) changes. Fluorescence measurements reveal the degradation of tyrosine residues. Mass spectrometry data complemented by RADACK calculations allow identifying all the oxidized amino-acids of the DNA binding domains of the proteins. Molecular dynamics simulations reveal and characterize the structural changes induced by the oxidation of each amino-acid in the headpiece. Most of the identified oxidized amino-acids are essential for the DNA-protein interaction as revealed by the analysis of the NMR- or crystallography-based structures of the complexes. Thus, irradiation can critically affect proteins properties and consequently can hinder their binding to DNA, due to the oxidation of amino-acids of the DNA-binding domain and to the subsequent conformational changes of it