Recruitment of ubiquitin-activating enzyme UBA1 to DNA by poly(ADP-ribose) promotes ATR signalling

The DNA damage response (DDR) ensures cellular adaptation to genotoxic insults. In the crowded environment of the nucleus, the assembly of productive DDR complexes requires multiple protein modifications. How the apical E1 ubiquitin activation enzyme UBA1 integrates spatially and temporally in the DDR remains elusive. Using a human cell-free system, we show that poly(ADP-ribose) polymerase 1 promotes the recruitment of UBA1 to DNA. We find that the association of UBA1 with poly(ADP-ribosyl)ated protein–DNA complexes is necessary for the phosphorylation replication protein A and checkpoint kinase 1 by the serine/threonine protein kinase ataxia-telangiectasia and RAD3-related, a prototypal response to DNA damage. UBA1 interacts directly with poly(ADP-ribose) via a solvent-accessible and positively charged patch conserved in the Animalia kingdom but not in Fungi. Thus, ubiquitin activation can anchor to poly(ADP-ribose)-seeded protein assemblies, ensuring the formation of functional ataxia-telangiectasia mutated and RAD3-related-signalling complexes

Mechanical Analysis of WEST divertor support plate

The Tore Supra tokamak is being transformed in an x-point divertor fusion device in the frame of the WEST (W-for tungsten-Environment in Steady-state Tokamak) project, launched in support to the ITER tungsten divertor strategy. The WEST project aims to test W monoblock Plasma Facing Units (PFU) under long plasma discharge (up to 1000s), with thermal loads of the same magnitude as those expected for ITER. Therefore the divertor is a key component of the WEST project, and so is its support structure, which has to handle strong mechanical loads. The WEST upper and lower divertor are made of 12 30° sectors, each one composed of 38 PFU that can be made of tungsten, CuCrZr or graphite. A generic 316L stainless steel 30° conic support plate is used to hold the 38 PFU together, regardless of their material. The PFUs are fixed on the support plate thanks to 152 Xm19 stainless steel fixing elements (4 per PFU), and in each of this fixing element an Aluminium-Nickel-Bronze alloy (Al-Ni-Br) pin is engaged in a slotted hole, in order to allow thermal expansion in the length direction of the PFU. The support plate is fixed on the divertor coil casing thanks to 10 M10 screws. Mechanicals loads which act on the PFUs are transmitted to the support plate through the fixing elements. These loads are due to Vertical Displacement Event (VDE), disruptions and thermal expansion of the PFU. First the different load cases, PFU configurations and scenario are presented. Then an ANSYS plastic mechanical simulation is performed in order to validate the number of cycles of the support plate for each scenario: 30 000 cycles in steady-state and 3000 cycles in VDE. Finally reactions forces from the previous ANSYS simulation are used in order to calculate the stress in the M10 screws

Label-free detection of anticancer drug paclitaxel in living cells by confocal Raman microscopy

Confocal Raman microscopy, a non-invasive, label-free, and high spatial resolution imaging technique is employed to trace the anticancer drug paclitaxel in living Michigan Cancer Foundation-7 (MCF-7) cells. The Raman images were treated by K-mean cluster analysis to detect the drug in cells. Distribution of paclitaxel in cells is verified by calculating the correlation coefficient between the reference spectrum of the drug and the whole Raman image spectra. A time dependent gradual diffusion of paclitaxel all over the cell is observed suggesting a complementary picture of the pharmaceutical action of this drug based on rapid binding of free tubulin to crystallized paclitaxel. (C) 2013 American Institute of Physics. [http://dx.doi.org/10.1063/1.4794871

Asymmetry of Magnetosheath Flows and Magnetopause Shape During Low Alfvén Mach Number Solar Wind

Previous works have emphasized the significant influence of the solar wind Alfvén Mach number (MA) on magnetospheric dynamics. Here we report statistical, observational results that pertain to changes in the magnetosheath flow distribution and magnetopause shape as a function of solar wind MA and interplanetary magnetic field (IMF) clock angle orientation. We use all Cluster 1 data in the magnetosheath during the period 2001–2010, using an appropriate spatial superposition procedure, to produce magnetosheath flow distributions as a function of location in themagnetosheath relative to the IMF and other parameters. The results demonstrate that enhanced flows in the magnetosheath are expected at locations quasi-perpendicular to the IMF direction in the plane perpendicular to the Sun-Earth line; in other words, for the special case of a northward IMF, enhanced flows are observed on the dawn and dusk flanks of the magnetosphere, while much lower flows are observed above the poles. The largest flows are adjacent to themagnetopause. Using appropriate magnetopause crossing lists (for both high and lowMA), we also investigate the changes inmagnetopause shape as a function of solarwindMA and IMF orientation. Comparing observed magnetopause crossings with predicted positions from an axisymmetric semi-empirical model, we statistically show that the magnetopause is generally circular during high MA, while is it elongated (albeit with moderate statistical significance) along the direction of the IMF during low MA. These findings are consistent with enhanced magnetic forces that prevail in the magnetosheath during lowMA. The component of the magnetic forces parallel to the magnetopause produces the enhanced flows along and adjacent to the magnetopause, while the component normal to the magnetopause exerts an asymmetric pressure on the magnetopause that deforms it into an elongated shape

Special Care and School Difficulties in 8-Year-Old Very Preterm Children: The Epipage Cohort Study

OBJECTIVES: To investigate school difficulties, special care and behavioral problems in 8 year-old very preterm (VPT) children. PATIENT AND METHODS: Longitudinal population-based cohort in nine regions of France of VPT children and a reference group born at 39-40 weeks of gestation (WG). The main outcome measures were information about school, special care and behavioral problems using Strengths and Difficulties Questionnaire from a questionnaire to parents. RESULTS: Among the 1439 VPT children, 5% (75/1439) were in a specialised school or class, 18% (259/1439) had repeated a grade in a mainstream class and 77% (1105/1439) were in the appropriate grade-level in mainstream class; these figures were 1% (3/327) , 5% (16/327) and 94% (308/327) , respectively, for the reference group. Also, 15% (221/1435) of VPT children in a mainstream class received support at school versus 5% (16/326) of reference group. More VPT children between the ages of five and eight years received special care (55% (794/1436)) than children born at term (38% (124/325)); more VPT children (21% (292/1387)) had behavioral difficulties than the reference group (11% (35/319)). School difficulties, support at school, special care and behavioral difficulties in VPT children without neuromotor or sensory deficits varied with gestational age, socioeconomic status, and cognitive score at the age of five. CONCLUSIONS: Most 8-year-old VPT children are in mainstream schools. However, they have a high risk of difficulty in school, with more than half requiring additional support at school and/or special care. Referral to special services has increased between the ages of 5 and 8 years, but remained insufficient for those with borderline cognitive scores

Design and RF measurements of a 5 GHz 500 kW window for the ITER LHCD system

International audienceCEA/IRFM is conducting R&D efforts in order to validate the critical RF components of the 5 GHz ITER LHCD system, which is expected to transmit 20 MW of RF power to the plasma. Two 5 GHz 500 kW BeO pill-box type window prototypes have been manufactured in 2012 by the PMB Company, in close collaboration with CEA/IRFM. Both windows have been validated at low power, showing good agreement between measured and modeling, with a return loss better than 32 dB and an insertion loss below 0.05 dB. This paper reports on the window RF design and the low power measurements. The high power tests up to 500kW have been carried out in March 2013 in collaboration with NFRI. Results of these tests are also reported. In the current ITER LHCD design, 20 MW Continuous Wave (CW) of Radio-Frequency power at 5 GHz are expected to be generated and transmitted to the plasma. In order to separate the vacuum vessel pressure from the cryostat waveguide pressure, forty eight 5 GHz 500kW CW windows are to be assembled on the waveguides at the equatorial port flange. For nuclear safety reasons, forty eight additional windows could be located in the cryostat section, to separate and monitor the cryostat waveguide pressure from the exterior transmission line pressure. These windows are identified as being one of the main critical components for the ITER LHCD system since first ITER LHCD studies [1] [2] [3] or more recently [4] [5] , and clearly require an important R&D effort. In this context and even if the LHCD system is not part of the construction baseline, the CEA/IRFM is conducting a R&D effort in order to validate a design and the performances of these RF windows. In order to begin the assessment of this need, two 5 GHz 500 kW/5 s pill-box type windows prototypes have been manufactured in 2012 by the PMB Company in close collaboration with the CEA/IRFM [6]. The section 2 of this paper reports the RF and mechanical design of a 5 GHz window. Some features of the mechanical design and the experimental RF measurements at low power are reported in section 3. High power results, made in collaboration with NFRI, are detailed in section 4. The development of CW windows is discussed in the conclusion. 2-RF AND MECHANICAL DESIGN The proposed 5 GHz RF window is based on a pill-box design [2] , i.e. a ceramic brazed in portion of a circular waveguide, connected on either side to a rectangular waveguide section. Typical design rules of thumb of such device are circular section diameter about the same size of the diagonal of the rectangular waveguide (cf. FIGURE 1). Without taking into account the ceramic, the circular section length is approximately half a guided wavelength of the circular TE 11 mode, in order for the device to act as a half-wave transformer. Once optimized, taking into account the ceramic, matching is correct only for a narrow band of frequency and is very sensitive to the device dimensions and the ceramic relative permittivity. The heat losses in the ceramic, which have to be extracted by an active water cooling, depends on the inside electric field topology and of ceramic dielectric loss (loss tangent). Undesirable modes due to parasitic resonances can be excited in the ceramic volume, raising the electric field an

Design and Tests of 500kW RF Windows for the ITER LHCD System

In the frame of a R\&D effort conducted by CEA toward the design and the qualification of a 5 GHz LHCD system for the ITER tokamak, two 5 GHz 500 kW/5 s windows have been designed, manufactured and tested at high power in collaboration with the National Fusion Research Institute (NFRI). The window design rely on a symmetrical pill-box concept with a cylindrical beryllium oxide ceramic brazed on an actively water cooled copper skirt. The ceramic RF properties have been measured on a test sample to get realistic values for guiding the design. Low power measurements of the manufactured windows show return losses below-32 dB and insertion losses between-0.01 dB and-0.05 dB, with an optimum frequency shifted toward lower frequencies. High power tests conducted at NFRI show unexpected total power loss for both windows. The ceramic temperature during RF pulses has been found to reach unexpected high temperature, preventing these windows to be used under CW conditions. A post-mortem RF analysis of samples taken from one window shows that the dielectric properties of the ceramic were not the ones measured on the manufacturer sample, which partly explain the differences with the reference modelling

Social Withdrawal Behaviour at One Year of Age Is Associated with Delays in Reaching Language Milestones in the EDEN Mother-Child Cohort Study

OBJECTIVE: The aim of the study was to examine the relationship between social withdrawal behaviour at one year and motor and language milestones. MATERIALS AND METHODS: One-year old children from the EDEN French population-based birth cohort study (Study on the pre- and postnatal determinants of the child’s development and prospective health Birth Cohort Study) were included. Social withdrawal at one year was assessed by trained midwives using the Alarm Distress BaBy (ADBB) scale. Midwives concurrently examined infants’ motor and language milestones. Parents reported on child’s psychomotor and language milestones, during the interview with the midwife. RESULTS: After adjusting for potential confounding factors, social withdrawal behaviour was significantly associated with concurrent delays in motor and language milestones assessed by the midwife or the parents. DISCUSSION: Higher scores on social withdrawal behaviour as assessed with the ADBB were associated with delays in reaching language milestones, and to a lesser extent with lower motor ability scores. Taking the contribution of social withdrawal behaviour into account may help understand the unfolding of developmental difficulties in children