The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM (-/-) patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Modelling of the effect of ELMs on fuel retention at the bulk W divertor of JET

Effect of ELMs on fuel retention at the bulk W target of JET ITER-Like Wall was studied with multi-scale calculations. Plasma input parameters were taken from ELMy H-mode plasma experiment. The energetic intra-ELM fuel particles get implanted and create near-surface defects up to depths of few tens of nm, which act as the main fuel trapping sites during ELMs. Clustering of implantation-induced vacancies were found to take place. The incoming flux of inter-ELM plasma particles increases the different filling levels of trapped fuel in defects. The temperature increase of the W target during the pulse increases the fuel detrapping rate. The inter-ELM fuel particle flux refills the partially emptied trapping sites and fills new sites. This leads to a competing effect on the retention and release rates of the implanted particles. At high temperatures the main retention appeared in larger vacancy clusters due to increased clustering rate

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Search for Extended Sources of Neutrino Emission in the Galactic Plane with IceCube

The Galactic plane, harboring a diffuse neutrino flux, is a particularly interesting target to study potential cosmic-ray acceleration sites. Recent gamma-ray observations by HAWC and LHAASO have presented evidence for multiple Galactic sources that exhibit a spatially extended morphology and have energy spectra continuing beyond 100 TeV. A fraction of such emission could be produced by interactions of accelerated hadronic cosmic rays, resulting in an excess of high-energy neutrinos clustered near these regions. Using 10 years of IceCube data comprising track-like events that originate from charged-current muon neutrino interactions, we perform a dedicated search for extended neutrino sources in the Galaxy. We find no evidence for time-integrated neutrino emission from the potential extended sources studied in the Galactic plane. The most significant location, at 2.6$\sigma$ post-trials, is a 1.7$^\circ$ sized region coincident with the unidentified TeV gamma-ray source 3HWC J1951+266. We provide strong constraints on hadronic emission from several regions in the Galaxy.Comment: 13 pages, 4 figures, 5 tables including an appendix. Accepted for publication in Astrophysical Journa

Measurement of atmospheric neutrino mixing with improved IceCube DeepCore calibration and data processing

We describe a new data sample of IceCube DeepCore and report on the latest measurement of atmospheric neutrino oscillations obtained with data recorded between 2011–2019. The sample includes significant improvements in data calibration, detector simulation, and data processing, and the analysis benefits from a sophisticated treatment of systematic uncertainties, with significantly greater level of detail since our last study. By measuring the relative fluxes of neutrino flavors as a function of their reconstructed energies and arrival directions we constrain the atmospheric neutrino mixing parameters to be sin2θ23=0.51±0.05 and Δm232=2.41±0.07×10−3  eV2, assuming a normal mass ordering. The errors include both statistical and systematic uncertainties. The resulting 40% reduction in the error of both parameters with respect to our previous result makes this the most precise measurement of oscillation parameters using atmospheric neutrinos. Our results are also compatible and complementary to those obtained using neutrino beams from accelerators, which are obtained at lower neutrino energies and are subject to different sources of uncertainties

Measurement of Atmospheric Neutrino Mixing with Improved IceCube DeepCore Calibration and Data Processing

We describe a new data sample of IceCube DeepCore and report on the latest measurement of atmospheric neutrino oscillations obtained with data recorded between 2011-2019. The sample includes significant improvements in data calibration, detector simulation, and data processing, and the analysis benefits from a detailed treatment of systematic uncertainties, with significantly higher level of detail since our last study. By measuring the relative fluxes of neutrino flavors as a function of their reconstructed energies and arrival directions we constrain the atmospheric neutrino mixing parameters to be $\sin^2\theta_{23} = 0.51\pm 0.05$ and $\Delta m^2_{32} = 2.41\pm0.07\times 10^{-3}\mathrm{eV}^2$, assuming a normal mass ordering. The resulting 40\% reduction in the error of both parameters with respect to our previous result makes this the most precise measurement of oscillation parameters using atmospheric neutrinos. Our results are also compatible and complementary to those obtained using neutrino beams from accelerators, which are obtained at lower neutrino energies and are subject to different sources of uncertainties

On the mechanisms governing gas penetration into a tokamak plasma during a massive gas injection

A new 1D radial fluid code, IMAGINE, is used to simulate the penetration of gas into a tokamak plasma during a massive gas injection (MGI). The main result is that the gas is in general strongly braked as it reaches the plasma, due to mechanisms related to charge exchange and (to a smaller extent) recombination. As a result, only a fraction of the gas penetrates into the plasma. Also, a shock wave is created in the gas which propagates away from the plasma, braking and compressing the incoming gas. Simulation results are quantitatively consistent, at least in terms of orders of magnitude, with experimental data for a D 2 MGI into a JET Ohmic plasma. Simulations of MGI into the background plasma surrounding a runaway electron beam show that if the background electron density is too high, the gas may not penetrate, suggesting a possible explanation for the recent results of Reux et al in JET (2015 Nucl. Fusion 55 093013)

Modelling of tungsten erosion and deposition in the divertor of JET-ILW in comparison to experimental findings

The erosion, transport and deposition of tungsten in the outer divertor of JET-ILW has been studied for an HMode discharge with low frequency ELMs. For this specific case with an inter-ELM electron temperature at the strike point of about 20 eV, tungsten sputtering between ELMs is almost exclusively due to beryllium impurity and self-sputtering. However, during ELMs tungsten sputtering due to deuterium becomes important and even dominates. The amount of simulated local deposition of tungsten relative to the amount of sputtered tungsten in between ELMs is very high and reaches values of 99% for an electron density of 5E13 cm$^{-3}$ at the strike point and electron temperatures between 10 and 30 eV. Smaller deposition values are simulated with reduced electron density. The direction of the B-field significantly influences the local deposition and leads to a reduction if the E×B drift directs towards the scrape-off-layer. Also, the thermal force can reduce the tungsten deposition, however, an ion temperature gradient of about 0.1 eV/mm or larger is needed for a significant effect. The tungsten deposition simulated during ELMs reaches values of about 98% assuming ELM parameters according to free-streaming model. The measured WI emission profiles in between and within ELMs have been reproduced by the simulation. The contribution to the overall net tungsten erosion during ELMs is about 5 times larger than the one in between ELMs for the studied case. However, this is due to the rather low electron temperature in between ELMs, which leads to deuterium impact energies below the sputtering threshold for tungsten

The effect of beryllium oxide on retention in JET ITER-like wall tiles

Preliminary results investigating the microstructure, bonding and effect of beryllium oxide formation on retention in the JET ITER-like wall beryllium tiles, are presented. The tiles have been investigated by several techniques: Scanning Electron Microscopy (SEM) equipped with Energy Dispersive X-ray (EDX), Transmission Electron microscopy (TEM) equipped with EDX and Electron Energy Loss Spectroscopy (EELS), Raman Spectroscopy and Thermal Desorption Spectroscopy (TDS). This paper focuses on results from melted materials of the dump plate tiles in JET. From our results and the literature, it is concluded, beryllium can form micron deep oxide islands contrary to the nanometric oxides predicted under vacuum conditions. The deepest oxides analyzed were up to 2-micron thicknesses. The beryllium Deuteroxide (BeOxDy) bond was found with Raman Spectroscopy. Application of EELS confirmed the oxide presence and stoichiometry. Literature suggests these oxides form at temperatures greater than 700 °C where self-diffusion of beryllium ions through the surface oxide layer can occur. Further oxidation is made possible between oxygen plasma impurities and the beryllium ions now present at the wall surface. Under Ultra High Vacuum (UHV) nanometric Beryllium oxide layers are formed and passivate at room temperature. After continual cyclic heating (to the point of melt formation) in the presence of oxygen impurities from the plasma, oxide growth to the levels seen experimentally (approximately two microns) is proposed. This retention mechanism is not considered to contribute dramatically to overall retention in JET, due to low levels of melt formation. However, this mechanism, thought the result of operation environment and melt formation, could be of wider concern to ITER, dependent on wall temperatures

Impact of fast ions on density peaking in JET : fluid and gyrokinetic modeling

The effect of fast ions on turbulent particle transport, driven by ion temperature gradient (ITG)/trapped electron mode turbulence, is studied. Two neutral beam injection (NBI) heated JET discharges in different regimes are analyzed at the radial position rho(t) = 0.6, one of them an L-mode and the other one an H-mode discharge. Results obtained from the computationally efficient fluid model EDWM and the gyro-fluid model TGLF are compared to linear and nonlinear gyrokinetic GENE simulations as well as the experimentally obtained density peaking. In these models, the fast ions are treated as a dynamic species with a Maxwellian background distribution. The dependence of the zero particle flux density gradient (peaking factor) on fast ion density, temperature and corresponding gradients, is investigated. The simulations show that the inclusion of a fast ion species has a stabilizing influence on the ITG mode and reduces the peaking of the main ion and electron density profiles in the absence of sources. The models mostly reproduce the experimentally obtained density peaking for the L-mode discharge whereas the H-mode density peaking is significantly underpredicted, indicating the importance of the NBI particle source for the H-mode density profile