Test Station for Magnetization Measurements on Large Quantities of Superconducting Strands

In the superconducting main magnets of the Large Hadron Collider (LHC), persistent currents in the superconductor determine the field quality at injection field. For this reason it is necessary to check the magnetization of the cable strands during their production. During four years, this requires measurements of the width of the strand magnetization hysteresis loop at 0.5 T, 1.9 K, at a rate of up to eight samples per day. This paper describes the design, construction and the first results of a magnetization test station built for this purpose. The samples are cooled in a cryostat, with a 2-m long elliptic tail. This tail is inserted in a normal conducting dipole magnet with a field between ± 1.5 T. Racetrack pick-up coils, integrated in the cryostat, detect the voltage due to flux change, which is then integrated numerically. The sample holder can contain eight strand samples, each 20 cm long. The test station operates in two modes: either the sample is fixed while the external field is changed, or the sample is moved while the field remains constant. First results of calibration measurements with nickel and niobium are reported

Observation of Top Quark Production in Proton-Nucleus Collisions

Peer reviewe

Identification and Transcriptionnal Regulation of the Mineralocorticoid Recepetor Target Genes in Renal Cells

Le récepteur minéralocorticoïde (MR), activé par l’aldostérone, exerce de nombreuses fonctions pléïotropes, notamment au niveau rénal où il régule l’homéostasie hydrosodée. Des dysfonctionnements de la signalisation minéralocorticoïde sont impliqués dans des pathologies majeures chez l’Homme. Dans ce travail, nous avons identifié par ChIP sequencing le premier cistrome du MR dans une lignée cellulaire rénale humaine. La caractérisation des cibles génomiques a permis de décrire l’élément de réponse spécifique du MR, et de démontrer l’existence de deux modes d’action pour le MR : par liaison directe à l’ADN, ou indirecte via la liaison à d’autres facteurs de transcription. Le MR est physiologiquement confronté à une dualité face au récepteur glucocorticoïde (GR) avec lequel il partage un ligand, le cortisol, et des cibles génomiques, dont le gène PER1. Sur ce dernier, les deux récepteurs se distinguent par des recrutements dynamiques et cycliques différents, variants selon l’hormone, et contemporains de celui de partenaires transcriptionnels, régulant ainsi des effets à court ou à long-terme. Enfin, par ChIP en série et en tandem, nous avons montré que le MR et le GR agissent sous forme d’homodimères ou d’hétérodimères.L’identification du cistrome du MR, et la caractérisation de ses mécanismes d’action moléculaires, améliore notre compréhension de la physiopathologie de la signalisation minéralocorticoïde, et pourrait aboutir, notamment par le développement d’antagonistes sélectifs du MR comme la Finérénone, à de nouvelles stratégies thérapeutiques.The mineralocorticoid receptor (MR), activated by aldosterone, exhibits numerous pleiotropic functions, most notably at the renal level where it regulates electrolytic homeostasis. Dysfunctions in the mineralocorticoid signaling pathway are involved in major diseases in Human. During this work, we have identified by ChIP sequencing the first MR cistrome in a human renal cell lineage. The characterization of the identified genomic targets allowed us to define a specific MR responsive element, and to demonstrate the existence of two transactivation processes for MR: through direct binding to DNA or through indirect interaction via binding to other transcription factors. MR is physiologically confronted with a duality with the glucocorticoid receptor (GR), since they share a common ligand, cortisol, and some of their genomic targets, whose PER1 gene. On the latter, MR and GR are distinguished by different dynamic and cyclical recruitment, varying according to hormone, and coordinated with the one of transcriptional partners, translating into the regulation of short-term and long-term effects. Finally, by serial and tandem ChIP experiment, we have demonstrated that MR and GR act as homodimer and as heterodimer.Identification of new MR genomic targets and characterization of its molecular mechanisms of action, improve our understanding of the pathophysiology of the mineralocorticoid signaling pathway. This could ultimately, notably through the development of selective MR antagonists like Finerenone, lead to new therapeutic strategies

Identification et régulation transcriptionnelle des gènes cibles du récepteur des minéralocorticoïdes dans les cellules rénales

The mineralocorticoid receptor (MR), activated by aldosterone, exhibits numerous pleiotropic functions, most notably at the renal level where it regulates electrolytic homeostasis. Dysfunctions in the mineralocorticoid signaling pathway are involved in major diseases in Human. During this work, we have identified by ChIP sequencing the first MR cistrome in a human renal cell lineage. The characterization of the identified genomic targets allowed us to define a specific MR responsive element, and to demonstrate the existence of two transactivation processes for MR: through direct binding to DNA or through indirect interaction via binding to other transcription factors. MR is physiologically confronted with a duality with the glucocorticoid receptor (GR), since they share a common ligand, cortisol, and some of their genomic targets, whose PER1 gene. On the latter, MR and GR are distinguished by different dynamic and cyclical recruitment, varying according to hormone, and coordinated with the one of transcriptional partners, translating into the regulation of short-term and long-term effects. Finally, by serial and tandem ChIP experiment, we have demonstrated that MR and GR act as homodimer and as heterodimer.Identification of new MR genomic targets and characterization of its molecular mechanisms of action, improve our understanding of the pathophysiology of the mineralocorticoid signaling pathway. This could ultimately, notably through the development of selective MR antagonists like Finerenone, lead to new therapeutic strategies.Le récepteur minéralocorticoïde (MR), activé par l’aldostérone, exerce de nombreuses fonctions pléïotropes, notamment au niveau rénal où il régule l’homéostasie hydrosodée. Des dysfonctionnements de la signalisation minéralocorticoïde sont impliqués dans des pathologies majeures chez l’Homme. Dans ce travail, nous avons identifié par ChIP sequencing le premier cistrome du MR dans une lignée cellulaire rénale humaine. La caractérisation des cibles génomiques a permis de décrire l’élément de réponse spécifique du MR, et de démontrer l’existence de deux modes d’action pour le MR : par liaison directe à l’ADN, ou indirecte via la liaison à d’autres facteurs de transcription. Le MR est physiologiquement confronté à une dualité face au récepteur glucocorticoïde (GR) avec lequel il partage un ligand, le cortisol, et des cibles génomiques, dont le gène PER1. Sur ce dernier, les deux récepteurs se distinguent par des recrutements dynamiques et cycliques différents, variants selon l’hormone, et contemporains de celui de partenaires transcriptionnels, régulant ainsi des effets à court ou à long-terme. Enfin, par ChIP en série et en tandem, nous avons montré que le MR et le GR agissent sous forme d’homodimères ou d’hétérodimères.L’identification du cistrome du MR, et la caractérisation de ses mécanismes d’action moléculaires, améliore notre compréhension de la physiopathologie de la signalisation minéralocorticoïde, et pourrait aboutir, notamment par le développement d’antagonistes sélectifs du MR comme la Finérénone, à de nouvelles stratégies thérapeutiques

Field mapping of large aperture superconducting quadrupoles

The three quadrupoles of a High Resolution Spectrometer (Jefferson Lab., hall A) were mapped using an array of 10 coils of well-defined geometry. The Q1 quadrupole has a 30 cm diameter bore and was measured over 1.6 m. The dimensions for Q2 and Q3 are 60 cm and 3.2 m. The results for Q1 are compared to an integral coil measurement. Detailed maps are extracted using a 3D harmonics analysis and the reference to filament models of the quadrupoles. The typical accuracy achieved is 0.1 mm (in radius) and 1 Gauss in the mapping volume, for a maximum field of 1.25 Tesla

Cistrome of the Aldosterone-activated Mineralocorticoid Receptor in Human Renal Cells: Cistrome of Human Renal Mineralocorticoid Receptor

International audienceAldosterone acts mainly by activating the mineralocorticoid receptor (MR), a transcription factor that regulates gene expression through complex and dynamic interactions with coregulators and transcriptional machinery, leading to fine-tuned control of vectorial ionic transport in the distal nephron. To identify genome-wide aldosterone-regulated MR targets in human renal cells, we set up the chromatin immunoprecipitation (ChIP) using a specific anti-MR antibody in a differentiated human renal cell line expressing GFP-MR. This approach coupled with high-throughput sequencing allowed identification of 974 genomic MR targets. Computational analysis identified a MR response element (MRE) including single or multiple half-sites and palindromic motifs in which the AGtACAgxatGTtCt sequence was the most prevalent motif. Most genomic MR binding sites (MBS) are located at distance >10 Kb from the transcriptional start sites of target genes (84%). Specific aldosterone-induced recruitment of MR on the first most relevant genomic sequences was further validated by ChIP-qPCR and correlated with concomitant and positive aldosterone-activated transcriptional regulation of the corresponding gene as assayed by RT-qPCR. Interestingly, most MBS lack MRE but harbor DNA recognition motifs for other transcription factors (FOX, EGR1, AP1, PAX5) suggesting functional interaction. This work provides new insights into aldosterone, MR-mediated renal signaling and opens relevant perspectives for mineralocorticoid-related pathophysiology

Field mapping of the Hall A high-resolution spectrometers of the Thomas Jefferson National Accelerator Facility (Jefferson Lab)

This paper reports on the magnetic field mapping performed on the HRS spectrometers of Hall A, which are of QQDQ type. The dipoles were measured with a set of Hall probes in the symmetry mid-plane. The quadrupoles were measured inside their whole volume by a set of axially segmented rotating coils. High accuracy has been reached in both cases. Dipoles and quadrupoles were measured for a set of ex citation currents covering the operating momentum range of the HRS: 0.5-4 GeV/c. The main results on field determination are presented

Antagonistic effects of finerenone and spironolactone on the aldosterone‐regulated transcriptome of human kidney cells

International audienceAldosterone, the main mineralocorticoid hormone in humans, plays a pivotal role in the control of water and salt reabsorption via activation of the mineralocorticoid receptor (MR). Alterations in MR signaling pathway lead to renal dysfunction, including chronic kidney disease and renal fibrosis, that can be prevented or treated with mineralocorticoid receptor antagonists (MRAs). Here, we used RNA-Sequencing to analyze effects of two MRAs, spironolactone and finerenone, on the aldosterone-induced transcriptome of a human renal cell line stably expressing the MR. Bioinformatics analysis of the data set reveals the identity of hundreds of genes induced or repressed by aldosterone. Their regulation is modulated in a time-dependent manner and, for the induced genes, depends on the aldosterone-driven direct binding of the MR onto its genomic targets that we have previously characterized. Although both MRAs block aldosterone-induced as well as aldosterone-repressed genes qualitatively similarly, finerenone has a quantitatively more efficient antagonism on some aldosterone-induced genes. Our data provide the first complete transcriptome for aldosterone on a human renal cell line and identifies pro-inflammatory markers (IL6, IL11, CCL7, and CXCL8) as aldosterone-repressed genes

Glucocorticoids stimulate hypothalamic dynorphin expression accounting for stress-induced impairment of GnRH secretion during preovulatory period

International audienc

Ulipristal Acetate Inhibits Progesterone Receptor Isoform A-Mediated Human Breast Cancer Proliferation and BCl₂-L₁ Expression

<div><p>The progesterone receptor (PR) with its isoforms and ligands are involved in breast tumorigenesis and prognosis. We aimed at analyzing the respective contribution of PR isoforms, PRA and PRB, in breast cancer cell proliferation in a new estrogen-independent cell based-model, allowing independent PR isoforms analysis. We used the bi-inducible human breast cancer cell system MDA-iPRAB. We studied the effects and molecular mechanisms of action of progesterone (P4) and ulipristal acetate (UPA), a new selective progesterone receptor modulator, alone or in combination. P4 significantly stimulated MDA-iPRA expressing cells proliferation. This was associated with P4-stimulated expression of the anti-apoptotic factor BCL₂-L₁ and enhanced recruitment of PRA, SRC-1 and RNA Pol II onto the +58 kb PR binding motif of the <i>BCL</i>_<i>2</i><i>-L</i>_<i>1</i> gene. UPA decreased cell proliferation and repressed BCL_2-L₁ expression in the presence of PRA, correlating with PRA and SRC1 but not RNA Pol II recruitment. These results bring new information on the mechanism of action of PR ligands in controlling breast cancer cell proliferation through PRA in an estrogen independent model. Evaluation of PR isoforms ratio, as well as molecular signature studies based on PRA target genes could be proposed to facilitate personalized breast cancer therapy. In this context, UPA could be of interest in endocrine therapy. Further confirmation in the clinical setting is required.</p></div