Homomeric GluA2(R) AMPA receptors can conduct when desensitized

Desensitization is a canonical property of ligand-gated ion channels, causing progressive current decline in the continued presence of agonist. AMPA-type glutamate receptors (AMPARs), which mediate fast excitatory signaling throughout the brain, exhibit profound desensitization. Recent cryo-EM studies of AMPAR assemblies show their ion channels to be closed in the desensitized state. Here we present evidence that homomeric Q/R-edited AMPARs still allow ions to flow when the receptors are desensitized. GluA2(R) expressed alone, or with auxiliary subunits (γ-2, γ-8 or GSG1L), generates large fractional steady-state currents and anomalous current-variance relationships. Our results from fluctuation analysis, single-channel recording, and kinetic modeling, suggest that the steady-state current is mediated predominantly by conducting desensitized receptors. When combined with crystallography this unique functional readout of a hitherto silent state enabled us to examine cross-linked cysteine mutants to probe the conformation of the desensitized ligand binding domain of functioning AMPAR complexes

Constraints on Nucleon Decay via "Invisible" Modes from the Sudbury Neutrino Observatory

Data from the Sudbury Neutrino Observatory have been used to constrain the lifetime for nucleon decay to ``invisible'' modes, such as n -> 3 nu. The analysis was based on a search for gamma-rays from the de-excitation of the residual nucleus that would result from the disappearance of either a proton or neutron from O16. A limit of tau_inv > 2 x 10^{29} years is obtained at 90% confidence for either neutron or proton decay modes. This is about an order of magnitude more stringent than previous constraints on invisible proton decay modes and 400 times more stringent than similar neutron modes.Comment: Update includes missing efficiency factor (limits change by factor of 2) Submitted to Physical Review Letter

The Distances of the Magellanic Clouds

The present status of our knowledge of the distances to the Magellanic Clouds is evaluated from a post-Hipparcos perspective. After a brief summary of the effects of structure, reddening, age and metallicity, the primary distance indicators for the Large Magellanic Cloud are reviewed: The SN 1987A ring, Cepheids, RR Lyraes, Mira variables, and Eclipsing Binaries. Distances derived via these methods are weighted and combined to produce final "best" estimates for the Magellanic Clouds distance moduli.Comment: Invited review article to appear in ``Post Hipparcos Cosmic Candles'', F. Caputo & A. Heck (Eds.), Kluwer Academic Publ., Dordrecht, in pres

Cosmogenic neutron production at the Sudbury Neutrino Observatory

Neutrons produced in nuclear interactions initiated by cosmic-ray muons present an irreducible background to many rare-event searches, even in detectors located deep underground. Models for the production of these neutrons have been tested against previous experimental data, but the extrapolation to deeper sites is not well understood. Here we report results from an analysis of cosmogenically produced neutrons at the Sudbury Neutrino Observatory. A specific set of observables are presented, which can be used to benchmark the validity of geant4 physics models. In addition, the cosmogenic neutron yield, in units of 10-4 cm2/(g·μ), is measured to be 7.28±0.09(stat)-1.12+1.59(syst) in pure heavy water and 7.30±0.07(stat)-1.02+1.40(syst) in NaCl-loaded heavy water. These results provide unique insights into this potential background source for experiments at SNOLAB

Virtual Blocks: a serious game for spatial ability improvement on mobile devices

This paper presents a novel spatial instruction system for improving spatial abilities of engineering students. A 3D mobile game application called Virtual Blocks has been designed to provide a 3D virtual environment to build models with cubes that help students to perform visualization tasks to promote the development of their spatial ability during a short remedial course. A validation study with 26 freshman engineering students at La Laguna University (Spain) has concluded that the training had a measurable and positive impact on students spatial ability. In addition, the results obtained using a satisfaction questionnaire show that Virtual Blocks is considered an easy to use and stimulating application.This work has been partially supported by the (Spanish) National Program for Studies and Analysis project "Evaluation and development of competencies associated to the spatial ability in the new engineering undergraduate courses" (Ref. EA2009-0025) and the (Spanish) National Science Project "Enhancing Spatial REasoning and VIsual Cognition with advanced technological tools (ESREVIC)" (Ref TIN2010-21296-C02-02)Martín Dorta, NN.; Sanchez Berriel, I.; Bravo, M.; Hernández, J.; Saorin, JL.; Contero, M. (2014). Virtual Blocks: a serious game for spatial ability improvement on mobile devices. Multimedia Tools and Applications. 73(3):1575-1595. https://doi.org/10.1007/s11042-013-1652-0S15751595733Baartmans BG, Sorby SA (1996) Introduction to 3-D spatial visualization. Prentice Hall, Englewood CliffsClements D, Battista M (1992) Geometry and spatial reasoning. In: Grouws DA (ed) Handbook of research on mathematics teaching and learning. New York, pp 420–464Cohen J (1988) Statistical power analysis for the behavioral sciences, 2nd edn. Erlbaum, HillsdaleDe Lisi R, Cammarano DM (1996) Computer experience and gender differences in undergraduate mental rotation performance. Comput Hum Behav 12:351–361Deno JA (1995) The relationship of previous experiences to spatial visualization ability. Eng Des Graph J 59(3):5–17Feng J, Spence I, Pratt J (2007) Playing an action video game reduces gender differences in spatial cognition. Psychol Sci 18(10):850–855French JW (1951) The description of aptitude and achievement tests in terms of rotated factors. Psychometric monograph 5Guilford JP, Lacy JI (1947) Printed classification tests, A.A.F. Aviation Psychological Progress Research Report, 5. US. Government Printing Office, Washington DCHalpern DF (2000) Sex differences and cognitive abilities. Erlbaum, MahwahHöfele C (2007) Mobile 3D graphics: learning 3D graphics with the Java Micro Edition. Editorial ThomsonKajiya JT, Kay TL (1989) Rendering fur with three dimensional textures. In Proceedings of the 16th Annual Conference on Computer Graphics and interactive Techniques SIGGRAPH ’89. ACM Press, New York pp 271–280Linn MC, Petersen AC (1985) Emergence and characterization of gender differences in spatial abilities: a meta-analysis. Child Dev 56:1479–1498Martin-Dorta N, Sanchez-Berriel I, Bravo M, Hernandez J, Saorin JL, Contero M (2010) A 3D educational mobile game to enhance student’s spatial skills, ICALT, pp.6–10, 2010 10th IEEE International Conference on Advanced Learning TechnologiesMartin-Dorta N, Saorin J, Contero M (2008) Development of a fast remedial course to improve the spatial abilities of engineering students. J Eng Educ 27(4):505–514Martin-Dorta N, Saorin JL, Contero M (2011) Web-based spatial training using handheld touch screen devices. Educ Technol Soc 14(3):163–177McGee MG (1979) Human spatial abilities: psychometric studies and environmental, genetic, hormonal, and neurological influences. Psychol Bull 86:889–918Noguera JM, Segura RJ, Ogayar CJ, Joan-Arinyo R (2011) Navigating large terrains using commodity mobile devices. Comput Geosci 37:1218–1233Okagaki L, Frensch PA (1994) Effects of video game playing on measures of spatial performance: gender effects in late adolescence. J Appl Dev Psychol 15(1):33–58Pulli K, Aarnio T, Miettinen V, Roimela K, Vaarala J (2007) Mobile 3D graphics with OpenGL ES and M3G. Editorial Morgan KaufmannQuaiser-Pohl C, Geiser C, Lehmann W (2005) The relationship between computer-game preference, gender, and mental-rotation ability. Personal Individ Differ 40(3):609–619Smith IM (1964) Spatial ability- its educational and social significance. The University of London Press, LondonSorby S (2007) Developing 3D spatial skills for engineering students. Australas Assoc Eng Educ 13(1):1–11Terlecki MS, Newcombe NS (2005) How important is the digital divide? The relation of computer and videogame usage to gender differences in mental rotation ability. Sex Roles 53(5/6):433–441Terlecki MS, Newcombe NS, Little M (2008) Durable and generalized effects of spatial experience on mental rotation: gender differences in growth patterns. Appl Cogn Psychol 22:996–1013Thurstone LL (1950) Some primary abilities in visual thinking (Tech. Rep. No. 59). IL University of Chicago Psychometric Laboratory, ChicagoThurstone LL, Thurstone TG (1941) Factorial studies of intelligence. Psychometric monographs. Chicago Press, ChicagoVanderberg S, Kuse A (1978) Mental Rotation, a group test of three dimensional spatial visualization. Percept Mot Skills 47:599–604Zimmerman WS (1954) Hypotheses concerning the nature of the spatial factors. Educ Psychol Meas 14:396–40

Histone Deacetylase 3 Depletion in Osteo/Chondroprogenitor Cells Decreases Bone Density and Increases Marrow Fat

Histone deacetylase (Hdac)3 is a nuclear enzyme that contributes to epigenetic programming and is required for embryonic development. To determine the role of Hdac3 in bone formation, we crossed mice harboring loxP sites around exon 7 of Hdac3 with mice expressing Cre recombinase under the control of the osterix promoter. The resulting Hdac3 conditional knockout (CKO) mice were runted and had severe deficits in intramembranous and endochondral bone formation. Calvarial bones were significantly thinner and trabecular bone volume in the distal femur was decreased 75% in the Hdac3 CKO mice due to a substantial reduction in trabecular number. Hdac3-CKO mice had fewer osteoblasts and more bone marrow adipocytes as a proportion of tissue area than their wildtype or heterozygous littermates. Bone formation rates were depressed in both the cortical and trabecular regions of Hdac3 CKO femurs. Microarray analyses revealed that numerous developmental signaling pathways were affected by Hdac3-deficiency. Thus, Hdac3 depletion in osterix-expressing progenitor cells interferes with bone formation and promotes bone marrow adipocyte differentiation. These results demonstrate that Hdac3 inhibition is detrimental to skeletal health

Discovery of molecular hydrogen in a high-velocity cloud of the Galactic halo

We report the discovery of molecular hydrogen absorption in a Galactic high-velocity cloud (HVC) in the direction of the Large Magellanic Cloud. For the same HVC we derive an iron abundance which is half of the solar value. Thus, all evidence points to a Galactic origin for high-velocity cloud complex in front of the LMC.Comment: Published in Nature, this week; 14 pages, 3 figure

Portable Optical Fiber Probe-Based Spectroscopic Scanner for Rapid Cancer Diagnosis: A New Tool for Intraoperative Margin Assessment

There continues to be a significant clinical need for rapid and reliable intraoperative margin assessment during cancer surgery. Here we describe a portable, quantitative, optical fiber probe-based, spectroscopic tissue scanner designed for intraoperative diagnostic imaging of surgical margins, which we tested in a proof of concept study in human tissue for breast cancer diagnosis. The tissue scanner combines both diffuse reflectance spectroscopy (DRS) and intrinsic fluorescence spectroscopy (IFS), and has hyperspectral imaging capability, acquiring full DRS and IFS spectra for each scanned image pixel. Modeling of the DRS and IFS spectra yields quantitative parameters that reflect the metabolic, biochemical and morphological state of tissue, which are translated into disease diagnosis. The tissue scanner has high spatial resolution (0.25 mm) over a wide field of view (10 cm×10 cm), and both high spectral resolution (2 nm) and high spectral contrast, readily distinguishing tissues with widely varying optical properties (bone, skeletal muscle, fat and connective tissue). Tissue-simulating phantom experiments confirm that the tissue scanner can quantitatively measure spectral parameters, such as hemoglobin concentration, in a physiologically relevant range with a high degree of accuracy (<5% error). Finally, studies using human breast tissues showed that the tissue scanner can detect small foci of breast cancer in a background of normal breast tissue. This tissue scanner is simpler in design, images a larger field of view at higher resolution and provides a more physically meaningful tissue diagnosis than other spectroscopic imaging systems currently reported in literatures. We believe this spectroscopic tissue scanner can provide real-time, comprehensive diagnostic imaging of surgical margins in excised tissues, overcoming the sampling limitation in current histopathology margin assessment. As such it is a significant step in the development of a platform technology for intraoperative management of cancer, a clinical problem that has been inadequately addressed to date.Case Comprehensive Cancer Center. Tissue Procurement, Histology and Immunohistochemistry Core Facility (P30 CA43703)National Cancer Institute (U.S.) (R01-CA140288)National Cancer Institute (U.S.) (R01-CA97966)National Center for Research Resources (U.S.) (S10-RR031845)National Center for Research Resources (U.S.) (P41-RR02594

An international survey of patients with thalassemia major and their views about sustaining life-long desferrioxamine use

BACKGROUND: Management of thalassemia major requires patients to have life-long access to a treatment regimen of regular blood transfusions coupled with iron chelation therapy. The objective of this study was to investigate patients' reasons for missing iron chelation therapy with desferrioxamine, and the support to sustain life-long adherence to treatment. METHODS: From October 1999 to May 2000 a survey of patients with thalassemia major was conducted in ten countries: Cyprus, Egypt, Greece, Hong Kong, India, Iran, Italy, Jordan, Taiwan, and the United States. RESULTS: 1,888 questionnaires (65%) were returned. Most patients (1,573) used desferrioxamine, and 79% administered a dose at least 4 days a week. Inaccessibility of the drug was a common reason for missing a dose in India (51%), and in Iran (25%), whereas, in any other country, it was a reason for less than 17% of patients. Overall, 58% reported reasons for missing a dose related to their beliefs or feelings about the medication, and 42% drug-related side effects. CONCLUSION: Many patients miss doses of desferrioxamine and an opportunity remains to develop interventions that provide more support to sustain use of desferrioxamine