136 research outputs found
Synthesis of estrogens in progenitor cells of adult fish brain: Evolutive novelty or exaggeration of a more general mechanism implicating estrogens in neurogenesis?
International audienceIn contrast to other vertebrates, in which the adult brain shows limited adult neurogenesis, teleost fishes exhibit an unparalleled capacity to generate new neurons as adults, suggesting that their brains present a highly permissive environment for the maintenance and proliferation of adult progenitors. Here, we examine the hypothesis that one of the factors permitting establishment of this favourable environment is estradiol. Indeed, recent data showed that radial glial cells strongly expressed one of two aromatase duplicated genes. Aromatase is the estrogen-synthesizing enzyme and this observation is of great interest, given that radial glial cells are progenitor cells capable of generating new neurons. Given the well-documented roles of estrogens on cell fate, and notably on cell proliferation, these data suggest that estradiol could be involved in maintaining and/or activating these progenitors. Examination of recent data in birds and mammals suggests that the situation in fish could well be an exaggeration of a more general mechanism implicating estrogens in neurogenesis. Indeed, there is accumulating evidence that estrogens are involved in embryonic, adult or reparative neurogenesis in other vertebrates, notably in mammals
Aromatase in the brain of teleost fish: expression, regulation and putative functions.
International audienceUnlike that of mammals, the brain of teleost fish exhibits an intense aromatase activity due to the strong expression of one of two aromatase genes (aromatase A or cyp19a1a and aromatase B or cyp19a1b) that arose from a gene duplication event. In situ hybridization, immunohistochemistry and expression of GFP (green fluorescent protein) in transgenic tg(cyp19a1b-GFP) fish demonstrate that aromatase B is only expressed in radial glial cells (RGC) of adult fish. These cells persist throughout life and act as progenitors in the brain of both developing and adult fish. Although aromatase B-positive radial glial cells are most abundant in the preoptic area and the hypothalamus, they are observed throughout the entire central nervous system and spinal cord. In agreement with the fact that brain aromatase activity is correlated to sex steroid levels, the high expression of cyp19a1b is due to an auto-regulatory loop through which estrogens and aromatizable androgens up-regulate aromatase expression. This mechanism involves estrogen receptor binding on an estrogen response element located on the cyp19a1b promoter. Cell specificity is achieved by a mandatory cooperation between estrogen receptors and unidentified glial factors. Given the emerging roles of estrogens in neurogenesis, the unique feature of the adult fish brain suggests that, in addition to classical functions on brain sexual differentiation and sexual behaviour, aromatase expression in radial glial cells could be part of the mechanisms authorizing the maintenance of a high proliferative activity in the brain of fish
Nuclear Progesterone Receptors Are Up-Regulated by Estrogens in Neurons and Radial Glial Progenitors in the Brain of Zebrafish
In rodents, there is increasing evidence that nuclear progesterone receptors are transiently expressed in many regions of the developing brain, notably outside the hypothalamus. This suggests that progesterone and/or its metabolites could be involved in functions not related to reproduction, particularly in neurodevelopment. In this context, the adult fish brain is of particular interest, as it exhibits constant growth and high neurogenic activity that is supported by radial glia progenitors. However, although synthesis of neuroprogestagens has been documented recently in the brain of zebrafish, information on the presence of progesterone receptors is very limited. In zebrafish, a single nuclear progesterone receptor (pgr) has been cloned and characterized. Here, we demonstrate that this pgr is widely distributed in all regions of the zebrafish brain. Interestingly, we show that Pgr is strongly expressed in radial glial cells and more weakly in neurons. Finally, we present evidence, based on quantitative PCR and immunohistochemistry, that nuclear progesterone receptor mRNA and proteins are upregulated by estrogens in the brain of adult zebrafish. These data document for the first time the finding that radial glial cells are preferential targets for peripheral progestagens and/or neuroprogestagens. Given the crucial roles of radial glial cells in adult neurogenesis, the potential effects of progestagens on their activity and the fate of daughter cells require thorough investigation
Immunological non-inferiority of a new fully liquid presentation of the MenACWY-CRM vaccine to the licensed vaccine : results from a randomized, controlled, observer-blind study in adolescents and young adult
A fully liquid MenACWY-CRM vaccine presentation has been developed, modifying the meningococcal serogroup A (MenA) component from lyophilized to liquid. The safety and immunogenicity of the liquid presentation at the end of the intended shelf-life (aged for 24 or 30 months) were compared to the licensed lyophilized/liquid presentation. This multicenter, randomized (1:1), observer-blind, phase 2b study (NCT03433482) enrolled adolescents and young adults (age 10-40 years). In part 1, 844 participants received one dose of liquid presentation stored for approximately 24 months or licensed presentation. In part 2, 846 participants received one dose of liquid presentation stored for approximately 30 months or licensed presentation. After storage, the MenA free saccharide (FS) level was approximately 25% and O-acetylation was approximately 45%. The primary objective was to demonstrate non-inferiority of the liquid presentation to licensed presentation, as measured by human serum bactericidal assay (hSBA) geometric mean titers (GMTs) against MenA, 1-month post-vaccination. Immune responses against each vaccine serogroup were similar between groups. Between-group ratios of hSBA GMTs for MenA were 1.21 (part 1) and 1.11 (part 2), with two-sided 95% confidence interval lower limits (0.94 and 0.87, respectively) greater than the prespecified non-inferiority margin (0.5), thus meeting the primary study objective. No safety concerns were identified. Despite reduced O-acetylation of MenA and increased FS content, serogroup-specific immune responses induced by the fully liquid presentation were similar to those induced by the licensed MenACWY-CRM vaccine, with non-inferior anti-MenA responses. The safety profiles of the vaccine presentations were similar.GlaxoSmithKline Biologicals SAhttps://www.tandfonline.com/journals/KHVIMedical Microbiolog
Natalizumab treatment shows low cumulative probabilities of confirmed disability worsening to EDSS milestones in the long-term setting.
Abstract Background Though the Expanded Disability Status Scale (EDSS) is commonly used to assess disability level in relapsing-remitting multiple sclerosis (RRMS), the criteria defining disability progression are used for patients with a wide range of baseline levels of disability in relatively short-term trials. As a result, not all EDSS changes carry the same weight in terms of future disability, and treatment benefits such as decreased risk of reaching particular disability milestones may not be reliably captured. The objectives of this analysis are to assess the probability of confirmed disability worsening to specific EDSS milestones (i.e., EDSS scores âĽ3.0, âĽ4.0, or âĽ6.0) at 288 weeks in the Tysabri Observational Program (TOP) and to examine the impact of relapses occurring during natalizumab therapy in TOP patients who had received natalizumab for âĽ24 months. Methods TOP is an ongoing, open-label, observational, prospective study of patients with RRMS in clinical practice. Enrolled patients were naive to natalizumab at treatment initiation or had received â¤3 doses at the time of enrollment. Intravenous natalizumab (300âŻmg) infusions were given every 4 weeks, and the EDSS was assessed at baseline and every 24 weeks during treatment. Results Of the 4161 patients enrolled in TOP with follow-up of at least 24 months, 3253 patients with available baseline EDSS scores had continued natalizumab treatment and 908 had discontinued (5.4% due to a reported lack of efficacy and 16.4% for other reasons) at the 24-month time point. Those who discontinued due to lack of efficacy had higher baseline EDSS scores (median 4.5 vs. 3.5), higher on-treatment relapse rates (0.82 vs. 0.23), and higher cumulative probabilities of EDSS worsening (16% vs. 9%) at 24 months than those completing therapy. Among 24-month completers, after approximately 5.5 years of natalizumab treatment, the cumulative probabilities of confirmed EDSS worsening by 1.0 and 2.0 points were 18.5% and 7.9%, respectively (24-week confirmation), and 13.5% and 5.3%, respectively (48-week confirmation). The risks of 24- and 48-week confirmed EDSS worsening were significantly higher in patients with on-treatment relapses than in those without relapses. An analysis of time to specific EDSS milestones showed that the probabilities of 48-week confirmed transition from EDSS scores of 0.0â2.0 to âĽ3.0, 2.0â3.0 to âĽ4.0, and 4.0â5.0 to âĽ6.0 at week 288 in TOP were 11.1%, 11.8%, and 9.5%, respectively, with lower probabilities observed among patients without on-treatment relapses (8.1%, 8.4%, and 5.7%, respectively). Conclusions In TOP patients with a median (range) baseline EDSS score of 3.5 (0.0â9.5) who completed 24 months of natalizumab treatment, the rate of 48-week confirmed disability worsening events was below 15%; after approximately 5.5 years of natalizumab treatment, 86.5% and 94.7% of patients did not have EDSS score increases of âĽ1.0 or âĽ2.0 points, respectively. The presence of relapses was associated with higher rates of overall disability worsening. These results were confirmed by assessing transition to EDSS milestones. Lower rates of overall 48-week confirmed EDSS worsening and of transitioning from EDSS score 4.0â5.0 to âĽ6.0 in the absence of relapses suggest that relapses remain a significant driver of disability worsening and that on-treatment relapses in natalizumab-treated patients are of prognostic importance
SDSS-III: Massive Spectroscopic Surveys of the Distant Universe, the Milky Way Galaxy, and Extra-Solar Planetary Systems
Building on the legacy of the Sloan Digital Sky Survey (SDSS-I and II),
SDSS-III is a program of four spectroscopic surveys on three scientific themes:
dark energy and cosmological parameters, the history and structure of the Milky
Way, and the population of giant planets around other stars. In keeping with
SDSS tradition, SDSS-III will provide regular public releases of all its data,
beginning with SDSS DR8 (which occurred in Jan 2011). This paper presents an
overview of the four SDSS-III surveys. BOSS will measure redshifts of 1.5
million massive galaxies and Lya forest spectra of 150,000 quasars, using the
BAO feature of large scale structure to obtain percent-level determinations of
the distance scale and Hubble expansion rate at z<0.7 and at z~2.5. SEGUE-2,
which is now completed, measured medium-resolution (R=1800) optical spectra of
118,000 stars in a variety of target categories, probing chemical evolution,
stellar kinematics and substructure, and the mass profile of the dark matter
halo from the solar neighborhood to distances of 100 kpc. APOGEE will obtain
high-resolution (R~30,000), high signal-to-noise (S/N>100 per resolution
element), H-band (1.51-1.70 micron) spectra of 10^5 evolved, late-type stars,
measuring separate abundances for ~15 elements per star and creating the first
high-precision spectroscopic survey of all Galactic stellar populations (bulge,
bar, disks, halo) with a uniform set of stellar tracers and spectral
diagnostics. MARVELS will monitor radial velocities of more than 8000 FGK stars
with the sensitivity and cadence (10-40 m/s, ~24 visits per star) needed to
detect giant planets with periods up to two years, providing an unprecedented
data set for understanding the formation and dynamical evolution of giant
planet systems. (Abridged)Comment: Revised to version published in The Astronomical Journa
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Research and Design of a Routing Protocol in Large-Scale Wireless Sensor Networks
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Transverse-momentum and pseudorapidity distributions of charged hadrons in pp collisions at âs=0.9 and 2.36 TeV
Measurements of inclusive charged-hadron transverse-momentum and pseudorapidity distributions are presented for proton-proton collisions at root s = 0.9 and 2.36 TeV. The data were collected with the CMS detector during the LHC commissioning in December 2009. For non-single-diffractive interactions, the average charged-hadron transverse momentum is measured to be 0.46 +/- 0.01 (stat.) +/- 0.01 (syst.) GeV/c at 0.9 TeV and 0.50 +/- 0.01 (stat.) +/- 0.01 (syst.) GeV/c at 2.36 TeV, for pseudorapidities between -2.4 and +2.4. At these energies, the measured pseudorapidity densities in the central region, dN(ch)/d eta vertical bar(vertical bar eta vertical bar and pp collisions. The results at 2.36 TeV represent the highest-energy measurements at a particle collider to date
Le traitement adjuvant du cancer du sein par tamoxifène. Entre risques et bÊnÊfices thÊrapeutiques
International audienceOne of the main tools available for making bio-medical decisions about the best treatment to prescribe is the risk-benefit ratio. This article takes a contextual approach to the decision-making processes involved in the prescription of adjuvant tamoxifen as a mean of reducing the risk of relapse of breast cancer. Using anthropological descriptive methods, it examines the discrepancy between patientsâ and doctorsâ perceptions of the risks and benefits of the treatment and analyses their underlying logics. Representations of women are related to cancer (fear of the disease), its treatment (efficacy) and tamoxifen (fear of hormones and aging), and can lead to a symbolic hierarchy of treatments, whereas doctorsâ professional practices focus mainly on the prevention of the recurrence of cancers.Uno de los elementos fundamentales para decidir una terapia es el balance riesgo-beneficio. Este articulo aborda el proceso de toma de decisiones que afecta al tratamiento de pacientes con cĂĄncer de seno. A partir de una perspectiva antropolĂłgica descriptiva, analizamos la prescripciĂłn de un tratamiento con tamoxifeno para reducir el riesgo de recidiva. Este trabajo explora el desajuste entre las percepciones de las pacientes y de los mĂŠdicos de los riesgos y beneficios del tratamiento, y analiza sus lĂłgicas cognitivas, simbolicas y sociales subyacentes. El articulo analiza las representaciones de las mujeres relativas al cancer (miedo a la enfermedad), a sus tratamientos (eficacia) y al tamoxifeno (miedo a las hormonas y al envejecimiento) que llevan a una jerarquizacion simbolica de los tratamientos. Los mĂŠdicos siguen una lĂłgica profesional de intervenciĂłn que privilegia la prevenciĂłn de la recidiva.La ÂŤ balance risque-bĂŠnĂŠfice Âť est l'un des piliers du processus dĂŠcisionnel biomĂŠdical conduisant Ă choisir une thĂŠrapeutique Ă administrer. Cet article se propose d'ĂŠclairer, en le contextualisant, le processus dĂŠcisionnel concernant le traitement de patientes atteintes d'un cancer du sein. Par une approche anthropologique descriptive de la prescription d'un traitement adjuvant par tamoxifène visant Ă rĂŠduire le risque de rĂŠcidive, il explore les dĂŠcalages entre l'apprĂŠhension des risques et des bĂŠnĂŠfices du traitement par les patientes et par les mĂŠdecins, et il analyse les logiques cognitives, symboliques et sociales qui les sous-tendent. Les reprĂŠsentations des femmes sont relatives au cancer (peur de la maladie), Ă ses traitements (efficacitĂŠ) et au tamoxifène (peur des hormones et du vieillissement) ; elles peuvent conduire Ă une hiĂŠrarchisation symbolique des traitements. Les mĂŠdecins, quant Ă eux, obĂŠissent Ă une logique professionnelle dâintervention dirigĂŠe prĂŠfĂŠrentiellement vers la prĂŠvention de la rĂŠcidive
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