Radiation Tests on the Complete System of the Instrumentation of the LHC Cryogenics at the CERN Neutrinos to Gran Sasso (CNGS) Test Facility

There are more than 6000 electronic cards for the instrumentation of the LHC cryogenics, housed in crates and distributed around the 27 km tunnel. Cards and crates will be exposed to a complex radiation field during the 10 years of LHC operation. Rad-tol COTS and rad-hard ASIC have been selected and individually qualified during the design phase of the cards. The test setup and the acquired data presented in this paper target the qualitative assessment of the compliance with the LHC radiation environment of an assembled system. It is carried out at the CNGS test facility which provides exposure to LHC-like radiation field

Myristic acid potentiates palmitic acid-induced lipotoxicity and steatohepatitis associated with lipodystrophy by sustaning de novo ceramide synthesis.

Palmitic acid (PA) induces hepatocyte apoptosis and fuels de novo ceramide synthesis in the endoplasmic reticulum (ER). Myristic acid (MA), a free fatty acid highly abundant in copra/palmist oils, is a predictor of nonalcoholic steatohepatitis (NASH) and stimulates ceramide synthesis. Here we investigated the synergism between MA and PA in ceramide synthesis, ER stress, lipotoxicity and NASH. Unlike PA, MA is not lipotoxic but potentiated PA-mediated lipoapoptosis, ER stress, caspase-3 activation and cytochrome c release in primary mouse hepatocytes (PMH). Moreover, MA kinetically sustained PA-induced total ceramide content by stimulating dehydroceramide desaturase and switched the ceramide profile from decreased to increased ceramide 14:0/ceramide16:0, without changing medium and long-chain ceramide species. PMH were more sensitive to equimolar ceramide14:0/ceramide16:0 exposure, which mimics the outcome of PA plus MA treatment on ceramide homeostasis, than to either ceramide alone. Treatment with myriocin to inhibit ceramide synthesis and tauroursodeoxycholic acid to prevent ER stress ameliorated PA plus MA induced apoptosis, similar to the protection afforded by the antioxidant BHA, the pan-caspase inhibitor z-VAD-Fmk and JNK inhibition. Moreover, ruthenium red protected PMH against PA and MA-induced cell death. Recapitulating in vitro findings, mice fed a diet enriched in PA plus MA exhibited lipodystrophy, hepatosplenomegaly, increased liver ceramide content and cholesterol levels, ER stress, liver damage, inflammation and fibrosis compared to mice fed diets enriched in PA or MA alone. The deleterious effects of PA plus MA-enriched diet were largely prevented by in vivo myriocin treatment. These findings indicate a causal link between ceramide synthesis and ER stress in lipotoxicity, and imply that the consumption of diets enriched in MA and PA can cause NASH associated with lipodystrophy

Galaxy cluster mass density profile derived using the submillimetre galaxies magnification bias

Context. The magnification bias is a gravitational lensing eect that produces an increase or decrease in the detection probability of background sources near the position of a lense. The special properties of the submillimetre galaxies (SMGs; steep source number counts, high redshift, and a very low cross-contamination with respect to the optical band) makes them the optimal background sample for magnification bias studies. Aims. We want to study the average mass density profile of tens to hundreds of clusters of galaxies acting as lenses that produce a magnification bias on the SMGs, and to estimate their associated masses and concentrations for dierent richness ranges. The cluster richness is defined as R = L200=L with L200 as the total r-band luminosity within the radius r200. Methods. The background sample is composed of SMGs observed by Herschel with 1:2 < z < 4:0 (mean redshift at 2:3) while the foreground sample is made up of galaxy clusters extracted from the Sloan Digital Sky Survey III with photometric redshifts of 0:05 < z < 0:8 (mean redshift at 0:38). Measurements are obtained by stacking the SMG–cluster pairs to estimate the crosscorrelation function using the Davis-Peebles estimator. This methodology allows us to derive the mass density profile for a wide range of angular scales, 2250 arcsec or 101300 kpc for z = 0:38, with a high radial resolution, and in particular to study the inner part of the dark matter halo (<100 kpc). In addition, we also divide the cluster sample into five bins of richness and we analyse the estimated cross-correlation data using dierent combinations of the most common theoretical mass density profiles. Results. It is impossible to fit the data with a single mass density profile at all scales: in the inner part there is a clear excess in the mass density profile with respect to the outer part that we interpret as the galactic halo of the big central galaxy. As for the outer part, the estimated average masses increase with richness from M200c = 5:8 1013 M to M200c = 51:5 1013 M (M200c = 7:1 1013 M for the total sample). With respect to the concentration parameter, its average also increases with richness from C = 0:74 to C = 1:74 (C = 1:72 for the total sample). In the small-scale regions, the obtained average masses fluctuate around M200c = 34 1013 M with average concentration values of around C 4. Conclusions. The total average masses are in perfect agreement with the mass–richness relationship estimated from the cluster catalogue. In the bins of lowest richness, the central galactic halo constitutes 40% of the total mass of the cluster and its relevance decreases for higher richness values. While the estimated average concentration values of the central galactic halos are in agreement with traditional mass–concentration relationships, we find low concentrations for the outer part. Moreover, the concentrations decrease for lower richness values, probably indicating that the group of galaxies cannot be considered to be relaxed systems. Finally, we notice a systematic lack of signal at the transition between the dominance of the cluster halo and the central galactic halo (100 kpc). This feature is also present in previous studies using dierent catalogues and/or methodologies, but is never discussed

First Experience with the LHC Cryogenic Instrumentation

The LHC under commissioning at CERN will be the world's largest superconducting accelerator and therefore makes extensive use of cryogenic instruments. These instruments are installed in the tunnel and therefore have to withstand the LHC environment that imposes radiation-tolerant design and construction. Most of the instruments require individual calibration; some of them exhibit several variants as concerns measuring span; all relevant data are therefore stored in an Oracle® database. Those data are used for the various quality assurance procedures defined for installation and commissioning, as well as for generating tables used by the control system to configure automatically the input/output channels. This paper describes the commissioning of the sensors and the corresponding electronics, the first measurement results during the cool-down of one machine sector; it discusses the different encountered problems and their corresponding solutions

Selective Fractionation And Isolation Of Allelopathic Compounds From Helianthus Annuus L. Leaves By Means Of High-Pressure Techniques

The allelopathic potential of Helianthus annuus L. leaves was study based on bio-directed chemical fractionation approach. Aerial parts of H. annuus were extracted by means of SFE using supercritical carbon dioxide (scCO2) and ESE using CO2+50% EtOH/H2O (varying ethanol in water from 0 to 100%). Extractions were carried out at 400 bar, 55 °C, 20 g/min and for 4 h. Then, extracts were fractionated in three separators at the following conditions: S1: 200 bar/45 °C; S2: 90 bar/40 °C; and S3: 1 atm/30 °C. ESE obtained higher overall yields than scCO2 and the use of water as cosolvent (CO2+50% H2O) resulted in a S3 fraction free from chlorophylls and rich in bioactive compounds. 14 compounds, including fatty acids, terpenes, flavonoids and heliannuols, were isolated from this fraction. After performing the bioassay on pure compounds, heliannuol D, tambulin, pinoresinol and sesquiterpene 10-oxo-isodauc-3-en-15-al showed the most effective inhibitor profiles

In the absence of ATPase activity, pre-RC formation is blocked prior to MCM2-7 hexamer dimerization

The origin recognition complex (ORC) of Saccharomyces cerevisiae binds origin DNA and cooperates with Cdc6 and Cdt1 to load the replicative helicase MCM2–7 onto DNA. Helicase loading involves two MCM2–7 hexamers that assemble into a double hexamer around double-stranded DNA. This reaction requires ORC and Cdc6 ATPase activity, but it is unknown how these proteins control MCM2–7 double hexamer formation. We demonstrate that mutations in Cdc6 sensor-2 and Walker A motifs, which are predicted to affect ATP binding, influence the ORC–Cdc6 interaction and MCM2–7 recruitment. In contrast, a Cdc6 sensor-1 mutant affects MCM2–7 loading and Cdt1 release, similar as a Cdc6 Walker B ATPase mutant. Moreover, we show that Orc1 ATP hydrolysis is not involved in helicase loading or in releasing ORC from loaded MCM2–7. To determine whether Cdc6 regulates MCM2–7 double hexamer formation, we analysed complex assembly. We discovered that inhibition of Cdc6 ATPase restricts MCM2–7 association with origin DNA to a single hexamer, while active Cdc6 ATPase promotes recruitment of two MCM2–7 hexamer to origin DNA. Our findings illustrate how conserved Cdc6 AAA+ motifs modulate MCM2–7 recruitment, show that ATPase activity is required for MCM2–7 hexamer dimerization and demonstrate that MCM2–7 hexamers are recruited to origins in a consecutive process

Inflammation, insulin resistance, and diabetes-mendelian randomization using CRP haplotypes points upstream

Background Raised C-reactive protein (CRP) is a risk factor for type 2 diabetes. According to the Mendelian randomization method, the association is likely to be causal if genetic variants that affect CRP level are associated with markers of diabetes development and diabetes. Our objective was to examine the nature of the association between CRP phenotype and diabetes development using CRP haplotypes as instrumental variables. Methods and Findings We genotyped three tagging SNPs (CRP + 2302G > A; CRP + 1444T > C; CRP + 4899T > G) in the CRP gene and measured serum CRP in 5,274 men and women at mean ages 49 and 61 y (Whitehall II Study). Homeostasis model assessment-insulin resistance (HOMA-IR) and hemoglobin A1c (HbA1c) were measured at age 61 y. Diabetes was ascertained by glucose tolerance test and self-report. Common major haplotypes were strongly associated with serum CRP levels, but unrelated to obesity, blood pressure, and socioeconomic position, which may confound the association between CRP and diabetes risk. Serum CRP was associated with these potential confounding factors. After adjustment for age and sex, baseline serum CRP was associated with incident diabetes (hazard ratio = 1.39 [95% confidence interval 1.29-1.51], HOMA-IR, and HbA1c, but the associations were considerably attenuated on adjustment for potential confounding factors. In contrast, CRP haplotypes were not associated with HOMA-IR or HbA1c (p=0.52-0.92). The associations of CRP with HOMA-IR and HbA1c were all null when examined using instrumental variables analysis, with genetic variants as the instrument for serum CRP. Instrumental variables estimates differed from the directly observed associations (p=0.007-0.11). Pooled analysis of CRP haplotypes and diabetes in Whitehall II and Northwick Park Heart Study II produced null findings (p=0.25-0.88). Analyses based on the Wellcome Trust Case Control Consortium (1,923 diabetes cases, 2,932 controls) using three SNPs in tight linkage disequilibrium with our tagging SNPs also demonstrated null associations. Conclusions Observed associations between serum CRP and insulin resistance, glycemia, and diabetes are likely to be noncausal. Inflammation may play a causal role via upstream effectors rather than the downstream marker CRP

The PAU Survey: Photometric redshifts using transfer learning from simulations

In this paper we introduce the \textsc{Deepz} deep learning photometric redshift (photo-$z$) code. As a test case, we apply the code to the PAU survey (PAUS) data in the COSMOS field. \textsc{Deepz} reduces the $\sigma_{68}$ scatter statistic by 50\% at $i_{\rm AB}=22.5$ compared to existing algorithms. This improvement is achieved through various methods, including transfer learning from simulations where the training set consists of simulations as well as observations, which reduces the need for training data. The redshift probability distribution is estimated with a mixture density network (MDN), which produces accurate redshift distributions. Our code includes an autoencoder to reduce noise and extract features from the galaxy SEDs. It also benefits from combining multiple networks, which lowers the photo-$z$ scatter by 10 percent. Furthermore, training with randomly constructed coadded fluxes adds information about individual exposures, reducing the impact of photometric outliers. In addition to opening up the route for higher redshift precision with narrow bands, these machine learning techniques can also be valuable for broad-band surveys.Comment: Accepted versio

Regulation of membrane ruffling by polarized STIM1 and ORAI1in cortactin-rich domains

La movilidad celular y la migración requieren la reorganización del citoesqueleto cortical en el borde principal de las células y la entrada de Ca2 + extracelular es esencial para esta reorganización. Sin embargo, la naturaleza molecular de los reguladores de esta vía es desconocida. Este trabajo contribuye a comprender el papel de STIM1 y ORAI1 en la promoción de la ondulación de la membrana al mostrar que la fosfo-STIM1 se localiza en el borde principal de las células, y que tanto phospho-STIM1 como ORAI1 se localizan conjuntamente con la cortactina (CTTN), un regulador del citoesqueleto en las zonas de rizo de la membrana. Las líneas celulares STIM1-KO y ORAI1-KO se generaron mediante la edición del genoma CRISPR / Cas9 en células U2OS. En ambos casos, las células KO presentaron una reducción notable de la entrada de Ca2 + operada por el almacén (SOCE) que se rescató mediante la expresión de STIM1-mCherry y ORAI1-mCherry. Estos resultados demostraron que SOCE regula la deformación de la membrana en el borde anterior de las células. Por otra parte, ORAI1 endógeno y ORAI1-GFP sobreexpresado coinmuno precipitado con CTTN endógeno. Este último resultado, además del fenotipo de las células KO, la preservación de la co-localización de ORAI1-CTTN durante el fruncido, y la inhibición de la rizo de la membrana por parte del inhibidor del canal de Ca2 + SKF96365, apoya aún más un vínculo funcional entre el SOCE y el fruncido de la membrana.Cell motility and migration requires the reorganization of the cortical cytoskeleton at the leading edge of cells and extracellular Ca2+ entry is essential for this reorganization. However the molecular nature of the regulators of this pathway is unknown. This work contributes to understanding the role of STIM1 and ORAI1 in the promotion of membrane ruffling by showing that phospho-STIM1 localizes at the leading edge of cells, and that both phospho-STIM1 and ORAI1 co-localize with cortactin (CTTN), a regulator of the cytoskeleton at membrane ruffling areas. STIM1-KO and ORAI1-KO cell lines were generated by CRISPR/Cas9 genome editing in U2OS cells. In both cases, KO cells presented a notable reduction of store-operated Ca2+ entry (SOCE) that was rescued by expression of STIM1-mCherry and ORAI1-mCherry. These results demonstrated that SOCE regulates membrane ruffling at the leading edge of cells. Moreover, endogenous ORAI1 and overexpressed ORAI1-GFP co-immuno precipitated with endogenous CTTN. This latter result, in addition to the KO cells’ phenotype, the preservation of ORAI1-CTTN co-localization during ruffling, and the inhibition of membrane ruffling g by the Ca2+- channel inhibitor SKF96365, further supports a functional link between SOCE and membrane ruffling.• Ministerio de Economía y Competitividad y Fondo Social Europeo. Becas BFU2011-22798 y BFU2014-52401-P, para Francisco Javier Martín Romero • Consejo de Investigación Médica. Beca MC_UU_12016 / 2, para Darío R. Alessi • Ministerio de Economía y Competitividad. Beca BES-2012-052061, para Aida María López Guerrero • Gobierno de Extremadura. Ayuda PD10081, para Patricia Tomás Martín • Ministerio de Educación, Cultura y Deporte. Beca FPU13 / 03430, para Carlos Pascual Caro • Consejo de Investigación Médica. Ayuda MR / K015869 / 1, para Graeme Ball • EMBO. Beca ASTF-311-2014, para Eulalia Pozo Guisado • Ministerio de Educación, Cultura Española y Deporte. Beca PRX14 / 00176, para Francisco Javier Martín RomeropeerReviewe