A Non-Linear Finite Element Model for the LHC Main Dipole Coil Cross-Section

The production of the dipole magnets for the Large Hadron Collider is at its final stage. Nevertheless, some mechanical instabilities are still observed for which no clear explanation has been found yet. A FE modelization of the dipole cold mass cross-section had already been developed at CERN, mainly for magnetic analysis, taking into account conductor blocks and a frictionless behavior. This paper describes a new ANSYS® model of the dipole coil cross-section, featuring individual turns inside conductor blocks, and implementing friction and the mechanical non-linear behavior of insulated cables. Preliminary results, comparison with measurements performed in industry and ongoing developments are discussed

Prenatal Insecticide Exposures and Birth Weight and Length among an Urban Minority Cohort

We reported previously that insecticide exposures were widespread among minority women in New York City during pregnancy and that levels of the organophosphate chlorpyrifos in umbilical cord plasma were inversely associated with birth weight and length. Here we expand analyses to include additional insecticides (the organophosphate diazinon and the carbamate propoxur), a larger sample size (n = 314 mother–newborn pairs), and insecticide measurements in maternal personal air during pregnancy as well as in umbilical cord plasma at delivery. Controlling for potential confounders, we found no association between maternal personal air insecticide levels and birth weight, length, or head circumference. For each log unit increase in cord plasma chlorpyrifos levels, birth weight decreased by 42.6 g [95% confidence interval (CI), −81.8 to −3.8, p = 0.03] and birth length decreased by 0.24 cm (95% CI, −0.47 to −0.01, p = 0.04). Combined measures of (ln)cord plasma chlorpyrifos and diazinon (adjusted for relative potency) were also inversely associated with birth weight and length (p < 0.05). Birth weight averaged 186.3 g less (95% CI, −375.2 to −45.5) among newborns with the highest compared with lowest 26% of exposure levels (p = 0.01). Further, the associations between birth weight and length and cord plasma chlorpyrifos and diazinon were highly significant (p ≤ 0.007) among newborns born before the 2000–2001 U.S. Environmental Protection Agency’s regulatory actions to phase out residential use of these insecticides. Among newborns born after January 2001, exposure levels were substantially lower, and no association with fetal growth was apparent (p > 0.8). The propoxur metabolite 2-isopropoxyphenol in cord plasma was inversely associated with birth length, a finding of borderline significance (p = 0.05) after controlling for chlorpyrifos and diazinon. Results indicate that prenatal chlorpyrifos exposures have impaired fetal growth among this minority cohort and that diazinon exposures may have contributed to the effects. Findings support recent regulatory action to phase out residential uses of the insecticides

Characterization of Molecular Determinants of the Conformational Stability of Macrophage Migration Inhibitory Factor: Leucine 46 Hydrophobic Pocket

Macrophage Migration Inhibitory Factor (MIF) is a key mediator of inflammatory responses and innate immunity and has been implicated in the pathogenesis of several inflammatory and autoimmune diseases. The oligomerization of MIF, more specifically trimer formation, is essential for its keto-enol tautomerase activity and probably mediates several of its interactions and biological activities, including its binding to its receptor CD74 and activation of certain signaling pathways. Therefore, understanding the molecular factors governing the oligomerization of MIF and the role of quaternary structure in modulating its structural stability and multifunctional properties is crucial for understanding the function of MIF in health and disease. Herein, we describe highly conserved intersubunit interactions involving the hydrophobic packing of the side chain of Leu46 onto the β-strand β3 of one monomer within a hydrophobic pocket from the adjacent monomer constituted by residues Arg11, Val14, Phe18, Leu19, Val39, His40, Val41, Val42, and Pro43. To elucidate the structural significance of these intersubunit interactions and their relative contribution to MIF’s trimerization, structural stability and catalytic activity, we generated three point mutations where Leu46 was replaced by glycine (L46G), alanine (L46A) and phenylalanine (L46F), and their structural properties, stability, oligomerization state, and catalytic activity were characterized using a battery of biophysical methods and X-ray crystallography. Our findings provide new insights into the role of the Leu46 hydrophobic pocket in stabilizing the conformational state of MIF in solution. Disrupting the Leu46 hydrophobic interaction perturbs the secondary and tertiary structure of the protein but has no effect on its oligomerization state

Performance of the First LHC Pre-series Superconducting Dipoles

Within the LHC magnet program, a preseries production of final design, full-scale superconducting dipoles has presently started in industry and magnets are being tested at CERN. The main features of these magnets are: two-in-one structure, 56 mm aperture, six-block two layer coils wound from 15.1 mm wide graded NbTi cables, and all-polyimide insulation. This paper reviews the main test results of magnets tested to date in both supercritical and superfluid helium. The results of the quench training, conductor performance, magnet protection, sensitivity to ramp rate, and magnetic field quality are presented and discussed in terms of the design parameters and the aims of the LHC magnet programme

Information Management within the LHC Hardware Commissioning Project

The core task of the commissioning of the LHC technical systems was the individual test of the 1572 superconducting circuits of the collider, the powering tests. The two objectives of these tests were the validation of the different sub-systems making each superconducting circuit as well as the validation of the superconducting elements of the circuits in their final configuration in the tunnel. A wide set of software applications were developed by the team in charge of coordinating the powering activities (Hardware Commissioning Coordination) in order to manage the amount of information required for the preparation, execution and traceability of the tests. In all the cases special care was taken in order to keep the tools consistent with the LHC quality assurance policy, avoid redundancies between applications, ensure integrity and coherence of the test results and optimise their usability within an accelerator operation environment. This paper describes the main characteristics of these tools; it details their positive impact on the completion on time of the LHC Hardware Commissioning Project and presents usage being envisaged during the coming years of operation of the LHC

Optimization of the powering tests of the LHC superconducting circuits

The Large Hadron Collider has (LHC) 1572 superconducting circuits which are distributed along the eight 3.5 km LHC sectors [1]. Time and resources during the commissioning of the LHC technical systems were mostly consumed by the powering tests of each circuit. The tests consisted in carrying out several powering cycles at different current levels for each superconducting circuit. The Hardware Commissioning Coordination was in charge of planning, following up and piloting the execution of the test program. The first powering test campaign was carried out in summer 2007 for sector 7-8 with an expected duration of 12 weeks. The experience gained during these tests was used by the commissioning team for minimising the duration of the following powering campaigns to comply with the stringent LHC project deadlines. Improvements concerned several areas: strategy, procedures, control tools, automatization, and resource allocation led to an average daily test rate increase from 25 to 200 tests per day. This paper describes these improvements and details their impact on the operation during the last months of LHC Hardware Commissioning

Dual role for ubiquitin in plant steroid hormone receptor endocytosis

Brassinosteroids are plant steroid hormones that control many aspects of plant growth and development, and are perceived at the cell surface by the plasma membrane-localized receptor kinase BRI1. Here we show that BRI1 is post-translationally modified by K63 polyubiquitin chains in vivo. Using both artificial ubiquitination of BRI1 and generation of an ubiquitination-defective BRI1 mutant form, we demonstrate that ubiquitination promotes BRI1 internalization from the cell surface and is essential for its recognition at the trans-Golgi network/early endosomes (TGN/EE) for vacuolar targeting. Finally, we demonstrate that the control of BRI1 protein dynamics by ubiquitination is an important control mechanism for brassinosteroid responses in plants. Altogether, our results identify ubiquitination and K63-linked polyubiquitin chain formation as a dual targeting signal for BRI1 internalization and sorting along the endocytic pathway, and highlight its role in hormonally controlled plant development

First Experimental Evidence of a Beam-Beam Long-Range Compensation Using Wires in the Large Hadron Collider

In high intensity and high energy colliders such as the CERN Large Hadron Collider and its future High Luminosity upgrade, interactions between the two beams around the different Interaction Points impose machine performance limitations. In fact, their effect reduces the beam lifetime and therefore the collider's luminosity reach. Those interactions are called Beam-Beam Long-Range interactions and a possible mitigation of their effect using DC wires was proposed for the first time in the early 2000's. This solution is currently being studied as an option for enhancing the HL-LHC performance. In 2017 and 2018, four demonstrators of wire compensators have been installed in the LHC. A two-year long experimental campaign followed in order to validate the possibility to mitigate the BBLR interactions in the LHC. During this campaign, a proof-of-concept was completed and motivated an additional set of experiments, successfully demonstrating the mitigation of BBLR interactions effects in beam conditions compatible with the operational configuration. This paper reports in detail the preparation of the experimental campaign, the obtained results and draws some perspectives for the future.Comment: Draft for a later PRAB submissio

Tetrahydrobiopterin Biosynthesis as an Off-Target of Sulfa Drugs

The introduction of sulfa drugs for the chemotherapy of bacterial infections in 1935 revolutionized medicine. Although their mechanism of action is understood, the molecular bases for most of their side effects remain obscure. Here, we report that sulfamethoxazole and other sulfa drugs interfere with tetrahydrobiopterin biosynthesis through inhibition of sepiapterin reductase. Crystal structures of sepiapterin reductase with bound sulfa drugs reveal how structurally diverse sulfa drugs achieve specific inhibition of the enzyme. The effect of sulfa drugs on tetrahydrobiopterin-dependent neurotransmitter biosynthesis in cell-based assays provides a rationale for some of their central nervous system related side effects, particularly in high-dose sutfamethoxazole therapy of Pneumorystis pneumonia. Our findings reveal an unexpected aspect of the pharmacology of sulfa drugs and might translate into their improved medical use