Epidermal growth factor receptor mediates the vascular dysfunction but not the remodeling induced by aldosterone/salt

Pathophysiological aldosterone (aldo)/mineralocorticoid receptor signaling has a major impact on the cardiovascular system, resulting in hypertension and vascular remodeling. Mineralocorticoids induce endothelial dysfunction, decreasing vasorelaxation in response to acetylcholine and increasing the response to vasoconstrictors. Activation of the epidermal growth factor receptor (EGFR) is thought to mediate the vascular effects of aldo, but this has yet to be demonstrated in vivo. In this study, we analyzed the molecular and functional vascular consequences of aldo-salt challenge in the waved 2 mouse, a genetic model with a partial loss of EGFR tyrosine kinase activity. Deficient EGFR activity is associated with global oxidative stress and endothelial dysfunction. A decrease in EGFR activity did not affect the arterial wall remodeling process induced by aldo-salt. By contrast, normal EGFR activity was required for the aldo-induced enhancement of phenylephrine- and angiotensin II-mediated vasoconstriction. In conclusion, this in vivo study demonstrates that EGFR plays a key role in aldosterone-mediated vascular reactivity

Erratum: The solar orbiter radio and plasma waves (RPW) instrument (Astronomy and Astrophysics (2020) 642 (A12) DOI: 10.1051/0004-6361/201936214)

The erratum concerns Fig. 9 entitled "Antenna radio-electrical properties" for which some of the parameters are not correct. The new figure with new parameters is provided in Fig. 1 of this corrigendum. Fig. 1. Corrected Antenna radio-electrical properties. (Figure Presented)

Neurosteroid biosynthetic pathways changes in prefrontal cortex in Alzheimer's disease.

Expression of the genes for enzymes involved in neurosteroid biosynthesis was studied in human prefrontal cortex (PFC) in the course of Alzheimer's disease (AD) (n=49). Quantitative RT-PCR (qPCR) revealed that mRNA levels of diazepam binding inhibitor (DBI), which is involved in the first step of steroidogenesis and in GABAergic transmission, were increased, as were mRNA levels for several neurosteroid biosynthetic enzymes. Aromatase, 17β-hydroxysteroid dehydrogenase type 1 (HSD17B1) and aldo-keto reductase 1C2 (AKR1C2), were all increased in the late stages of AD. Several GABA-A subunits were significantly reduced in AD. Increased expression of aromatase in the PFC was confirmed by immunohistochemistry and was found to be localized predominantly in astrocytes. These data suggest a role for estrogens and allopregnanolone produced by astrocytes in the PFC in AD, possibly as part of a rescue program. The reduced gene expression of some synaptic and extra-synaptic GABA-A subunits may indicate a deficit of modulation of GABA-A receptors by neuroactive steroids, which may contribute to the neuropsychiatric characteristics of this diseas

First results from the SCM search-coil magnetometer onboard Parker Solar Probe

International audienceThe SCM search-coil magnetometer measures AC magnetic fields with three components from 10 Hz to 50 kHz, and one component from 1 kHz to 1 MHz. The instrument was designed to properly observe the turbulent cascade of the solar wind in the inertial range and at kinetic scales, whistler waves and their role in the evolution of the electron distribution function, transients generated by shocks, etc. Here we report on the science objectives, the performance of the instrument, its calibration, the challenges that await us and the data products that will come out of it

First results from the SCM search-coil magnetometer onboard Parker Solar Probe

International audienceThe SCM search-coil magnetometer measures AC magnetic fields with three components from 10 Hz to 50 kHz, and one component from 1 kHz to 1 MHz. The instrument was designed to properly observe the turbulent cascade of the solar wind in the inertial range and at kinetic scales, whistler waves and their role in the evolution of the electron distribution function, transients generated by shocks, etc. Here we report on the science objectives, the performance of the instrument, its calibration, the challenges that await us and the data products that will come out of it

Genomic Alterations and Radioresistance in Breast Cancer: An Analysis of the Profiler Protocol

International audiencePurpose/Objective(s)Breast cancer (BC) patients with comparable prognostic features have heterogeneous outcomes, partly because of radiotherapy resistance leading to loco-regional recurrences (LRR). The ProfiLER (Profilage LYric et Région, NCT01774409) clinical trial aims at establishing a simple genetic profile of metastatic cancers in order to offer patients personalized molecular targeted therapies. In the breast cancer area, the genomic profiling of a population who ultimately became metastatic, and its correlation with the patient outcome years after LRR, provided an opportunity to identify post hoc biomarkers of the initial radiation resistance. The aim of the present study was to determine if specific tumor genetic alterations were associated with radiation resistance, defined as a LRR despite optimal surgery, radiotherapy, and systemic adjuvant therapies, in a ProfiLER series.Materials/MethodsGenetic profile of 162 BC patients’ tumors included in ProfiLER between 2013 and 2016 were analyzed using Next-Generation-Sequencing and Comparative-Genomic-Hybridization tests. Patients and tumor characteristics were analyzed for association with genomic rearrangements (mutations, amplification, homozygous deletions). Only gene alterations observed in >3% of the tumors, or included in well-known molecular pathways (PI3 Kinases pathway, MAP Kinases pathway, Tyrosine Kinase receptors family) were selected. The Cox multivariate analysis was based on (P3% of tumors. PIK3CA and ROS1 mutations were statistically correlated to the risk of LRR. A median loco-regional progression free survival (LRPFS) of 19.8 years was reported for PIK3CA mutation carriers (n = 34, 21%) versus 9.1 years for wild-type patients (HR = 0.29, 95% CI = 0.13-0.64, P = 0.002 in univariate analysis). PIK3CA mutation was identified as an independent protective factor of LRR using multivariate analysis (HR = 0.27, 95% CI = 0.09-0.82), P = 0.02). ROS1 mutated cancer patients (n = 8, 4.9%) had a median LRPFS of 4 years versus 16.1 years for wild-type patients (HR = 2.5, 95% CI = 1.74-7.05, P = 0.08 in univariate analysis), but was not identified as an independent LRR risk factor (HR = 2.45 95% CI = 0.83-7.26, P = 0.11 in multivariate analysis). Other mutations and amplifications were not associated with LRR. Among relapsing patients, the median time to LRR was nearly significantly different regarding status of the PIK3CA mutations, with 8.6 years for mutated patients versus4.7 years for non-mutated patients (P = 0.09).ConclusionPIK3CA mutation was associated with a lower risk of LRR in this BC population. ROS1 mutation was marginally associated with a higher risk of LRR, possibly because of a limited population. Results suggest PIK3CA and ROS1to be possible biomarkers of radio-sensitivity

Measurement of magnetic field fluctuations in the Parker Solar Probe and Solar Orbiter missions

International audienceThe search‐coil magnetometer (SCM) measures the magnetic signature of solar wind fluctuations with three components in the 3 Hz – 50 kHz range and one single component in the 1 kHz – 1 MHz range. This instrument is important for providing in situ observations of transients caused by interplanetary shocks and reconnection, for the identification of electromagnetic wave modes in plasmas and the determination of their characteristics (planarity, polarization, ellipticity and k‐vector) and for studying the turbulent cascade in the kinetic range. Two similar triaxial search‐coils have been built for the Parker Solar Probe and Solar Orbiter missions. Here we describe the science objectives of both missions which led to the SCM design and present the characteristics of the two instruments

Sexual dimorphic evolution of metabolic programming in non-genetic non-alimentary mild metabolic syndrome model in mice depends on feed-back mechanisms integrity for pro-opiomelanocortin-derived endogenous substances

Previously, we showed that our post-natal handling model induces pro-opiomelanocortin-derived (POMC) endogenous systems alterations in male mice at weaning. These alterations last up to adult age, and are at the basis of adult hormonal and metabolic conditions similar to mild metabolic syndrome/type-2 diabetes. Here, we evaluate how sex influences post-natal programming in these metabolic conditions. Subjects are adult control (non-handled) female (NHF) and male (NHM) CD-1 mice; adult post-natal handled female (HF) and male (HM) mice. Handling consists of daily maternal separation (10 min) plus sham injection, from birth to weaning (21 days). In adult handled males (90-days old) we find not only POMC-derived hormones alterations (enhanced basal plasma corticosterone (+91%) and ACTH (+109%)) but also overweight (+5.4%), fasting hyperglycemia (+40%), hypertriglyceridemia (+21%), enhanced brain mRNA expression of hydroxysteroid(11-beta)dehydrogenase type-1 (HSD11B1) (+49%), and decreased mRNA-HSD11B2 (-39%). Conversely, uric acid, creatinine, HDL(C), total cholesterol, glucose and insulin incremental area under-the-curve are not affected. In females, post-natal handling does not produce both hormonal and dysmetabolic diabetes-like changes; but handling enhances n3- and n6-poly-unsaturated, and decreases saturated fatty acids content in erythrocyte membrane composition in HF versus NHF. In conclusion, for the first time we show that female sex in mice exerts effective protection against the hypothalamus-pituitary-adrenal homeostasis disruption induced by our post-natal handling model on POMC cleavage products; endocrine disruption is in turn responsible for altered metabolic programming in male mice. The role of sex hormones is still to be elucidated