Alzheimer-associated presenilin-2 confers increased sensitivity to poptosis in PC12 cells

AbstractPresenilin-2 is a gene of unknown function recently identified based upon linkage with some forms of familial Alzheimer's disease. To investigate potential effects of PS-2 on cell viability, rat pheochromocytoma (PC12) cells were stably transfected with cDNA constructs encoding either full-length human PS-2 or, for comparison, mouse Bcl-xL. Overexpression of PS-2 conferred increased sensitivity to the apoptotic stimuli staurosporine and hydrogen peroxide. In contrast, Bcl-xL overexpression significantly reduced cell death induced by these stimuli. These results suggest that one function of PS-2 may involve modulation of cell viability

Continuous versus Cyclic Progesterone Exposure Differentially Regulates Hippocampal Gene Expression and Functional Profiles

This is the published version. Copyright 2012 Public Library of Science.This study investigated the impact of chronic exposure to continuous (CoP4) versus cyclic progesterone (CyP4) alone or in combination with 17β-estradiol (E2) on gene expression profiles targeting bioenergetics, metabolism and inflammation in the adult female rat hippocampus. High-throughput qRT-PCR analyses revealed that ovarian hormonal depletion induced by ovariectomy (OVX) led to multiple significant gene expression alterations, which were to a great extent reversed by co-administration of E2 and CyP4. In contrast, co-administration of E2 and CoP4 induced a pattern highly resembling OVX. Bioinformatics analyses further revealed clear disparities in functional profiles associated with E2+CoP4 and E2+CyP4. Genes involved in mitochondrial energy (ATP synthase α subunit; Atp5a1), redox homeostasis (peroxiredoxin 5; Prdx5), insulin signaling (insulin-like growth factor I; Igf1), and cholesterol trafficking (liver X receptor α subtype; Nr1h3), differed in direction of regulation by E2+CoP4 (down-regulation relative to OVX) and E2+CyP4 (up-regulation relative to OVX). In contrast, genes involved in amyloid metabolism (β-secretase; Bace1) differed only in degree of regulation, as both E2+CoP4 and E2+CyP4 induced down-regulation at different efficacy. E2+CyP4-induced changes could be associated with regulation of progesterone receptor membrane component 1(Pgrmc1). In summary, results from this study provide evidence at the molecular level that differing regimens of hormone therapy (HT) can induce disparate gene expression profiles in brain. From a translational perspective, confirmation of these results in a model of natural menopause, would imply that the common regimen of continuous combined HT may have adverse consequences whereas a cyclic combined regimen, which is more physiological, could be an effective strategy to maintain neurological health and function throughout menopausal aging

Progesterone Receptors: Form and Function in Brain

Emerging data indicate that progesterone has multiple non-reproductive functions in the central nervous system to regulate cognition, mood, inflammation, mitochondrial function, neurogenesis and regeneration, myelination and recovery from traumatic brain injury. Progesterone-regulated neural responses are mediated by an array of progesterone receptors (PR) that include the classic nuclear PRA and PRB receptors and splice variants of each, the seven transmembrane domain 7TMPRβ and the membrane-associated 25-Dx PR (PGRMC1). These PRs induce classic regulation of gene expression while also transducing signaling cascades that originate at the cell membrane and ultimately activate transcription factors. Remarkably, PRs are broadly expressed throughout the brain and can be detected in every neural cell type. The distribution of PRs beyond hypothalamic borders, suggests a much broader role of progesterone in regulating neural function. Despite the large body of evidence regarding progesterone regulation of reproductive behaviors and estrogen-inducible responses as well as effects of progesterone metabolite neurosteroids, much remains to be discovered regarding the functional outcomes resulting from activation of the complex array of PRs in brain by gonadally and/or glial derived progesterone. Moreover, the impact of clinically used progestogens and developing selective PR modulators for targeted outcomes in brain is a critical avenue of investigation as the non-reproductive functions of PRs have far-reaching implications for hormone therapy to maintain neurological health and function throughout menopausal aging

Supplementary Materials for U-Th dating of carbonate crusts reveals Neanderthal origin of Iberian cave art

Materiales suplementarios al artículo de Science 2018 sobre las dataciones de arte rupestre en la Península Ibérica mediante U-TH

Multi-core fibre-fed integral field spectrograph (MCIFU) IV:The fiber link

The Multi-Core Integral-Field Unit (MCIFU) is a diffraction-limited near-infrared integral-field spectrograph designed to detect and characterise exoplanets and disks in combination with extreme adaptive optics (xAO) instruments. It has been developed by an extended consortium as an experimental path finder for medium resolution spectroscopic upgrades for xAO systems. To allow it to achieve its goals we manufactured a fibre link system composed of a custom integrated fiber, with 3D printed microlenses and an ultrafast laser inscribed reformatter. Here we detail the specific requirements of the fibre link, from its design parameters, through its manufacture the laboratory performance and discuss upgrades for the future. © 2020 SPIE.Immediate accessThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Fasting-mimicking diet cycles reduce neuroinflammation to attenuate cognitive decline in Alzheimer's models

The effects of fasting-mimicking diet (FMD) cycles in reducing many aging and disease risk factors indicate it could affect Alzheimer's disease (AD). Here, we show that FMD cycles reduce cognitive decline and AD pathology in E4FAD and 3xTg AD mouse models, with effects superior to those caused by protein restriction cycles. In 3xTg mice, long-term FMD cycles reduce hippocampal Aβ load and hyperphosphorylated tau, enhance genesis of neural stem cells, decrease microglia number, and reduce expression of neuroinflammatory genes, including superoxide-generating NADPH oxidase (Nox2). 3xTg mice lacking Nox2 or mice treated with the NADPH oxidase inhibitor apocynin also display improved cognition and reduced microglia activation compared with controls. Clinical data indicate that FMD cycles are feasible and generally safe in a small group of AD patients. These results indicate that FMD cycles delay cognitive decline in AD models in part by reducing neuroinflammation and/or superoxide production in the brain

The Oxygen Paradox, the French Paradox, and age-related diseases

open46openDavies, Joanna M. S.; Cillard, Josiane; Friguet, Bertrand; Cadenas, Enrique; Cadet, Jean; Cayce, Rachael; Fishmann, Andrew; Liao, David; Bulteau, Anne-Laure; Derbré, Frédéric; Rébillard, Amélie; Burstein, Steven; Hirsch, Etienne; Kloner, Robert A.; Jakowec, Michael; Petzinger, Giselle; Sauce, Delphine; Sennlaub, Florian; Limon, Isabelle; Ursini, Fulvio; Maiorino, Matilde; Economides, Christina; Pike, Christian J.; Cohen, Pinchas; Salvayre, Anne Negre; Halliday, Matthew R.; Lundquist, Adam J.; Jakowec, Nicolaus A.; Mechta-Grigoriou, Fatima; Mericskay, Mathias; Mariani, Jean; Li, Zhenlin; Huang, David; Grant, Ellsworth; Forman, Henry J.; Finch, Caleb E.; Sun, Patrick Y.; Pomatto, Laura C. D.; Agbulut, Onnik; Warburton, David; Neri, Christian; Rouis, Mustapha; Cillard, Pierre; Capeau, Jacqueline; Rosenbaum, Jean; Davies, Kelvin J. A.Davies, Joanna M. S.; Cillard, Josiane; Friguet, Bertrand; Cadenas, Enrique; Cadet, Jean; Cayce, Rachael; Fishmann, Andrew; Liao, David; Bulteau, Anne-Laure; Derbré, Frédéric; Rébillard, Amélie; Burstein, Steven; Hirsch, Etienne; Kloner, Robert A.; Jakowec, Michael; Petzinger, Giselle; Sauce, Delphine; Sennlaub, Florian; Limon, Isabelle; Ursini, Fulvio; Maiorino, Matilde; Economides, Christina; Pike, Christian J.; Cohen, Pinchas; Salvayre, Anne Negre; Halliday, Matthew R.; Lundquist, Adam J.; Jakowec, Nicolaus A.; Mechta-Grigoriou, Fatima; Mericskay, Mathias; Mariani, Jean; Li, Zhenlin; Huang, David; Grant, Ellsworth; Forman, HENRY J.; Finch, Caleb E.; Sun, Patrick Y.; Pomatto, Laura C. D.; Agbulut, Onnik; Warburton, David; Neri, Christian; Rouis, Mustapha; Cillard, Pierre; Capeau, Jacqueline; Rosenbaum, Jean; Davies, Kelvin J. A

Multi-core fibre-fed integral-field unit (MCIFU):Overview and first-light

The Multi-Core Integral-Field Unit (MCIFU) is a new diffraction-limited near-infrared integral-field unit for exoplanet atmosphere characterization with extreme adaptive optics (xAO) instruments. It has been developed as an experimental pathfinder for spectroscopic upgrades for SPHERE+/VLT and other xAO systems. The wavelength range covers 1.0 um to 1.6um at a resolving power around 5000 for 73 points on-sky. The MCIFU uses novel astrophotonic components to make this very compact and robust spectrograph. We performed the first successful on-sky test with CANARY at the 4.2 meter William Herschel Telescope in July 2019, where observed standard stars and several stellar binaries. An improved version of the MCIFU will be used with MagAO-X, the new extreme adaptive optics system at the 6.5 meter Magellan Clay telescope in Chile. We will show and discuss the first-light performance and operations of the MCIFU at CANARY and discuss the integration of the MCIFU with MagAO-X.</p

Geometric and algebraic classification of quadratic differential systems with invariant hyperbolas

Let QSH be the whole class of non-degenerate planar quadratic differential systems possessing at least one invariant hyperbola. We classify this family of systems, modulo the action of the group of real affine transformations and time rescaling, according to their geometric properties encoded in the configurations of invariant hyperbolas and invariant straight lines which these systems possess. The classification is given both in terms of algebraic geometric invariants and also in terms of affine invariant polynomials and it yields a total of 205 distinct such configurations. We have 162 configurations for the subclass QSH(η>0) of systems which possess three distinct real singularities at infinity, and 43 configurations for the subclass QSH(η=0) of systems which possess either exactly two distinct real singularities at infinity or the line at infinity filled up with singularities. The algebraic classification, based on the invariant polynomials, is also an algorithm which makes it possible to verify for any given real quadratic differential system if it has invariant hyperbolas or not and to specify its configuration of invariant hyperbolas and straight lines