Galectin-4 Controls Intestinal Inflammation by Selective Regulation of Peripheral and Mucosal T Cell Apoptosis and Cell Cycle

Galectin-4 is a carbohydrate-binding protein belonging to the galectin family. Here we provide novel evidence that galectin-4 is selectively expressed and secreted by intestinal epithelial cells and binds potently to activated peripheral and mucosal lamina propria T-cells at the CD3 epitope. The carbohydrate-dependent binding of galectin-4 at the CD3 epitope is fully functional and inhibited T cell activation, cycling and expansion. Galectin-4 induced apoptosis of activated peripheral and mucosal lamina propria T cells via calpain-, but not caspase-dependent, pathways. Providing further evidence for its important role in regulating T cell function, galectin-4 blockade by antisense oligonucleotides reduced TNF-alpha inhibitor induced T cell death. Furthermore, in T cells, galectin-4 reduced pro-inflammatory cytokine secretion including IL-17. In a model of experimental colitis, galectin-4 ameliorated mucosal inflammation, induced apoptosis of mucosal T-cells and decreased the secretion of pro-inflammatory cytokines. Our results show that galectin-4 plays a unique role in the intestine and assign a novel role of this protein in controlling intestinal inflammation by a selective induction of T cell apoptosis and cell cycle restriction. Conclusively, after defining its biological role, we propose Galectin-4 is a novel anti-inflammatory agent that could be therapeutically effective in diseases with a disturbed T cell expansion and apoptosis such as inflammatory bowel disease

Dynein-Dynactin Complex Is Essential for Dendritic Restriction of TM1-Containing Drosophila Dscam

BACKGROUND: Many membrane proteins, including Drosophila Dscam, are enriched in dendrites or axons within neurons. However, little is known about how the differential distribution is established and maintained. METHODOLOGY/PRINCIPAL FINDINGS: Here we investigated the mechanisms underlying the dendritic targeting of Dscam[TM1]. Through forward genetic mosaic screens and by silencing specific genes via targeted RNAi, we found that several genes, encoding various components of the dynein-dynactin complex, are required for restricting Dscam[TM1] to the mushroom body dendrites. In contrast, compromising dynein/dynactin function did not affect dendritic targeting of two other dendritic markers, Nod and Rdl. Tracing newly synthesized Dscam[TM1] further revealed that compromising dynein/dynactin function did not affect the initial dendritic targeting of Dscam[TM1], but disrupted the maintenance of its restriction to dendrites. CONCLUSIONS/SIGNIFICANCE: The results of this study suggest multiple mechanisms of dendritic protein targeting. Notably, dynein-dynactin plays a role in excluding dendritic Dscam, but not Rdl, from axons by retrograde transport

Glycobiology of cell death: when glycans and lectins govern cell fate

Although one typically thinks of carbohydrates as associated with cell growth and viability, glycosylation also has an integral role in many processes leading to cell death. Glycans, either alone or complexed with glycan-binding proteins, can deliver intracellular signals or control extracellular processes that promote initiation, execution and resolution of cell death programs. Herein, we review the role of glycans and glycan-binding proteins as essential components of the cell death machinery during physiologic and pathologic settings.Fil: Lichtenstein, Rachel. Ben-Gurion University of the Negev. Faculty of Engineering. Department of Biotechnology Engineering; IsraelFil: Rabinovich, Gabriel Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. Universidad de Buenos Aires. Facultad de Cs.exactas y Naturales. Departamento de Quimica Biologica; Argentin

Sensitivity of the T2K accelerator-based neutrino experiment with an Extended run to 20×102120\times10^{21} POT

18 pages, 4 figures18 pages, 4 figures18 pages, 4 figures18 pages, 4 figures18 pages, 4 figuresRecent measurements at the T2K experiment indicate that CP violation in neutrino mixing may be observed in the future by long-baseline neutrino oscillation experiments. We explore the physics program of an extension to the currently approved T2K running of $7.8\times 10^{21}$ protons-on-target to $20\times 10^{21}$ protons-on-target,aiming at initial observation of CP violation with 3$\,\sigma$ or higher significance for the case of maximum CP violation. With accelerator and beam line upgrades, as well as analysis improvements, this program would occur before the next generation of long-baseline neutrino oscillation experiments that are expected to start operation in 2026.We acknowledge the support of MEXT, Japan; NSERC (Grant No. SAPPJ-2014-00031), NRC and CFI, Canada; CEA and CNRS/IN2P3, France; DFG, Germany; INFN, Italy; National Science Centre (NCN), Poland; RSF, RFBR and MES, Russia; MINECO and ERDF funds, Spain; SNSF and SERI, Switzerland; STFC, UK; and DOE, USA. We also thank CERN for the UA1/NOMAD magnet, DESY for the HERA-B magnet mover system, NII for SINET4, the WestGrid and SciNet consortia in Compute Canada, and GridPP in the United Kingdom. In addition, participation of individual researchers and institutions has been further supported by funds from ERC (FP7), H2020 Grant No. RISE-GA644294-JENNIFER, EU; JSPS, Japan; Royal Society, UK; and the DOE Early Career program, USA. CNRS/IN2P3: Centre National de la Recherche ScientifiqueInstitut National de Physique Nucleaire et de Physique des Particules RSF: Russian Science Foundation MES: Ministry of Education and Science, Russia ERDF: European Regional Development Fund SNSF: Swiss National Science Foundation SER (should be SERI): State Secretariat for Education, Research and Innovatio

Clinical Use and Therapeutic Potential of IVIG/SCIG, Plasma-Derived IgA or IgM, and Other Alternative Immunoglobulin Preparations

Intravenous and subcutaneous immunoglobulin preparations, consisting of IgG class antibodies, are increasingly used to treat a broad range of pathological conditions, including humoral immune deficiencies, as well as acute and chronic inflammatory or autoimmune disorders. A plethora of Fab- or Fc-mediated immune regulatory mechanisms has been described that might act separately or in concert, depending on pathogenesis or stage of clinical condition. Attempts have been undertaken to improve the efficacy of polyclonal IgG preparations, including the identification of relevant subfractions, mild chemical modification of molecules, or modification of carbohydrate side chains. Furthermore, plasma-derived IgA or IgM preparations may exhibit characteristics that might be exploited therapeutically. The need for improved treatment strategies without increase in plasma demand is a goal and might be achieved by more optimal use of plasma-derived proteins, including the IgA and the IgM fractions. This article provides an overview on the current knowledge and future strategies to improve the efficacy of regular IgG preparations and discusses the potential of human plasma-derived IgA, IgM, and preparations composed of mixtures of IgG, IgA, and IgM

Proposal for an Extended Run of T2K to 20×102120\times10^{21} POT

68 pages, 31 figures68 pages, 31 figures68 pages, 31 figuresRecent measurements by the T2K neutrino oscillation experiment indicate that CP violation in neutrino mixing may be observed in the future by long-baseline neutrino oscillation experiments. We propose an extension to the currently approved T2K running from 7.8\times 10^{21}~\mbox{POT} to 20\times 10^{21}~\mbox{POT}, aiming at initial observation of CP violation with 3$\,\sigma$ or higher significance for the case of maximum CP violation. The program also contains a measurement of mixing parameters, $\theta_{23}$ and $\Delta m^2_{32}$, with a precision of 1.7$^\circ$ or better and 1%, respectively. With accelerator and beamline upgrades, as well as analysis improvements, this program would occur before the next generation of long-baseline neutrino oscillation experiments that are expected to start operation in 2026

Measurement of the single pi(0) production rate in neutral current neutrino interactions on water

The single π0 production rate in neutral current neutrino interactions on water in a neutrino beam with a peak neutrino energy of 0.6 GeV has been measured using the PØD, one of the subdetectors of the T2K near detector. The production rate was measured for data taking periods when the PØD contained water (2.64×10(20) protons-on-target) and also periods without water (3.49×10(20) protons-on-target). A measurement of the neutral current single π0 production rate on water is made using appropriate subtraction of the production rate with water in from the rate with water out of the target region. The subtraction analysis yields 106 ± 41 ± 69 signal events where the uncertainties are statistical (stat.) and systematic (sys.) respectively. This is consistent with the prediction of 157 events from the nominal simulation. The measured to expected ratio is 0.68 ± 0.26 (stat) ± 0.44 (sys) ± 0.12 (flux). The nominal simulation uses a flux integrated cross section of 7.63×10(−39)cm(2) per nucleon with an average neutrino interaction energy of 1.3 GeV

First Measurement of the Muon Neutrino Charged Current Single Pion Production Cross Section on Water with the T2K Near Detector

The T2K off-axis near detector, ND280, is used to make the first differential cross section measurements of muon neutrino charged current single positive pion production on a water target at energies ${\sim}0.8$ GeV. The differential measurements are presented as a function of muon and pion kinematics, in the restricted phase-space defined by $p_{\pi^+}>200$MeV/c, $p_{\mu^-}>200$MeV/c, $\cos \theta_{\pi^+}>0.3$ and $\cos \theta_{\mu^-}>0.3$. The total flux integrated $\nu_\mu$ charged current single positive pion production cross section on water in the restricted phase-space is measured to be $\langle\sigma\rangle_\phi=4.25\pm0.48 (\mathrm{stat})\pm1.56 (\mathrm{syst})\times10^{-40} \mathrm{cm}^{2}/\mathrm{nucleon}$. The total cross section is consistent with the NEUT prediction ($5.03\times10^{-40} \mathrm{cm}^{2}/\mathrm{nucleon}$) and 2$\sigma$ lower than the GENIE prediction ($7.68\times10^{-40} \mathrm{cm}^{2}/\mathrm{nucleon}$). The differential cross sections are in good agreement with the NEUT generator. The GENIE simulation reproduces well the shapes of the distributions, but over-estimates the overall cross section normalization

Characterization of nuclear effects in muon-neutrino scattering on hydrocarbon with a measurement of final-state kinematics and correlations in charged-current pionless interactions at T2K

This paper reports measurements of final-state proton multiplicity, muon and proton kinematics, and their correlations in charged-current pionless neutrino interactions, measured by the T2K ND280 near detector in its plastic scintillator (C8H8) target. The data were taken between years 2010 and 2013, corresponding to approximately 6 × 1020 protons on target. Thanks to their exploration of the proton kinematics and of imbalances between the proton and muon kinematics, the results offer a novel probe of the nuclear-medium effects most pertinent to the (sub-)GeV neutrino-nucleus interactions that are used in accelerator-based long-baseline neutrino oscillation measurements. These results are compared to many neutrino-nucleus interaction models which all fail to describe at least part of the observed phase space. In case of events without a proton above a detection threshold in the final state, a fully consistent implementation of the local Fermi gas model with multinucleon interactions gives the best description of the data. In the case of at least one proton in the final state, the spectral function model agrees well with the data, most notably when measuring the kinematic imbalance between the muon and the proton in the plane transverse to the incoming neutrino. Within the models considered, only the existence of multinucleon interactions are able to describe the extracted cross section within regions of high transverse kinematic imbalance. The effect of final-state interactions is also discussed