Zeroth-order design report for the next linear collider. Volume 1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Raubenheimer, T.O.

1996-05-01

This Zeroth Order Design Report (ZDR) for the Next Linear Collider (NLC) has been completed as a feasibility study for a TeV-scale linear collider that incorporates a room-temperature accelerator powered by rf microwaves at 11.424 GHz--similar to that presently used in the SLC, but at four times the rf frequency. The purpose of this study is to examine the complete systems of such a collider, to understand how the parts fit together, and to make certain that every required piece has been included. The design presented here is not fully engineered in any sense, but to be assured that themore » NLC can be built, attention has been given to a number of critical components and issues that present special challenges. More engineering and development of a number of mechanical and electrical systems remain to be done, but the conclusion of this study is that indeed the NLC is technically feasible and can be expected to reach the performance levels required to perform research at the TeV energy scale. Volume one covers the following: the introduction; electron source; positron source; NLC damping rings; bunch compressors and prelinac; low-frequency linacs and compressors; main linacs; design and dynamics; and RF systems for main linacs.« less

The mammalian phosphate carrier SLC25A3 is a mitochondrial copper transporter required for cytochrome c oxidase biogenesis

PubMed Central

Boulet, Aren; Vest, Katherine E.; Maynard, Margaret K.; Gammon, Micah G.; Russell, Antoinette C.; Mathews, Alexander T.; Cole, Shelbie E.; Zhu, Xinyu; Phillips, Casey B.; Kwong, Jennifer Q.; Dodani, Sheel C.; Leary, Scot C.; Cobine, Paul A.

2018-01-01

Copper is required for the activity of cytochrome c oxidase (COX), the terminal electron-accepting complex of the mitochondrial respiratory chain. The likely source of copper used for COX biogenesis is a labile pool found in the mitochondrial matrix. In mammals, the proteins that transport copper across the inner mitochondrial membrane remain unknown. We previously reported that the mitochondrial carrier family protein Pic2 in budding yeast is a copper importer. The closest Pic2 ortholog in mammalian cells is the mitochondrial phosphate carrier SLC25A3. Here, to investigate whether SLC25A3 also transports copper, we manipulated its expression in several murine and human cell lines. SLC25A3 knockdown or deletion consistently resulted in an isolated COX deficiency in these cells, and copper addition to the culture medium suppressed these biochemical defects. Consistent with a conserved role for SLC25A3 in copper transport, its heterologous expression in yeast complemented copper-specific defects observed upon deletion of PIC2. Additionally, assays in Lactococcus lactis and in reconstituted liposomes directly demonstrated that SLC25A3 functions as a copper transporter. Taken together, these data indicate that SLC25A3 can transport copper both in vitro and in vivo. PMID:29237729

Opportunities and challenges of a low-energy positron source in the LERF

NASA Astrophysics Data System (ADS)

Benson, Stephen; Wojtsekhowski, Bogdan; Vlahovic, Branislav; Golge, Serkan

2018-05-01

Though there are many applications of low energy positrons, many experiments are source limited. Using the LERF accelerator at the Thomas Jefferson National Accelerator Facility, it is possible to build a high brightness source of very low-energy positrons. The accelerator requirements are well within the capabilities of the installed hardware. The accelerator can produce 120 kW of beam with a beam energy of up to 170 MeV. For these experiments, we only need run at up to 120 MeV. The gamma-to-positron converter must be able to absorb 20% of the beam power that the linac delivers. At this low an energy the converter, though challenging, is possible. The transport of the low energy positrons from the production target to the next stage, where the energy is reduced even further, must have a very large acceptance to be able to efficiently transport the flux of positrons from the positron production target to the moderator. We propose to accomplish such a transport by means of a guiding solenoidal field with a novel endcap design. In this presentation, we will present the proposed schemes necessary to realize such a high brightness positron source.

Functional Genomics of Attention-Deficit/ Hyperactivity Disorder (ADHD) Risk Alleles on Dopamine Transporter Binding in ADHD and Healthy Control Subjects

PubMed Central

Spencer, Thomas J.; Biederman, Joseph; Faraone, Stephen V.; Madras, Bertha K.; Bonab, Ali A.; Dougherty, Darin D.; Batchelder, Holly; Clarke, Allison; Fischman, Alan J.

2013-01-01

Background The main aim of this study was to examine the relationship between dopamine transporter (DAT) binding in the striatum in individuals with and without attention-deficit/hyperactivity disorder (ADHD), attending to the 3′-untranslated region of the gene (3′-UTR) and intron8 variable number of tandem repeats (VNTR) polymorphisms of the DAT (SLC6A3) gene. Methods Subjects consisted of 68 psychotropic (including stimulant)-naïve and smoking-naïve volunteers between 18 and 55 years of age (ADHD n = 34; control subjects n = 34). Striatal DAT binding was measured with positron emission tomography with 11C altropane. Genotyping of the two DAT (SLC6A3) 3′-UTR and intron8 VNTRs used standard protocols. Results The gene frequencies of each of the gene polymorphisms assessed did not differ between the ADHD and control groups. The ADHD status (t = 2.99; p < .004) and 3′-UTR of SLC6A3 9 repeat carrier status (t = 2.74; p < .008) were independently and additively associated with increased DAT binding in the caudate. The ADHD status was associated with increased striatal (caudate) DAT binding regardless of 3′-UTR genotype, and 3′-UTR genotype was associated with increased striatal (caudate) DAT binding regardless of ADHD status. In contrast, there were no significant associations between polymorphisms of DAT intron8 or the 3′-UTR-intron8 haplotype with DAT binding. Conclusions The 3′-UTR but not intron8 VNTR genotypes were associated with increased DAT binding in both ADHD patients and healthy control subjects. Both ADHD status and the 3′-UTR polymorphism status had an additive effect on DAT binding. Our findings suggest that an ADHD risk polymorphism (3′-UTR) of SLC6A3 has functional consequences on central nervous system DAT binding in humans. PMID:23273726

The mammalian phosphate carrier SLC25A3 is a mitochondrial copper transporter required for cytochrome c oxidase biogenesis.

PubMed

Boulet, Aren; Vest, Katherine E; Maynard, Margaret K; Gammon, Micah G; Russell, Antoinette C; Mathews, Alexander T; Cole, Shelbie E; Zhu, Xinyu; Phillips, Casey B; Kwong, Jennifer Q; Dodani, Sheel C; Leary, Scot C; Cobine, Paul A

2018-02-09

Copper is required for the activity of cytochrome c oxidase (COX), the terminal electron-accepting complex of the mitochondrial respiratory chain. The likely source of copper used for COX biogenesis is a labile pool found in the mitochondrial matrix. In mammals, the proteins that transport copper across the inner mitochondrial membrane remain unknown. We previously reported that the mitochondrial carrier family protein Pic2 in budding yeast is a copper importer. The closest Pic2 ortholog in mammalian cells is the mitochondrial phosphate carrier SLC25A3. Here, to investigate whether SLC25A3 also transports copper, we manipulated its expression in several murine and human cell lines. SLC25A3 knockdown or deletion consistently resulted in an isolated COX deficiency in these cells, and copper addition to the culture medium suppressed these biochemical defects. Consistent with a conserved role for SLC25A3 in copper transport, its heterologous expression in yeast complemented copper-specific defects observed upon deletion of PIC2 Additionally, assays in Lactococcus lactis and in reconstituted liposomes directly demonstrated that SLC25A3 functions as a copper transporter. Taken together, these data indicate that SLC25A3 can transport copper both in vitro and in vivo . © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Intense source of slow positrons

NASA Astrophysics Data System (ADS)

Perez, P.; Rosowsky, A.

2004-10-01

We describe a novel design for an intense source of slow positrons based on pair production with a beam of electrons from a 10 MeV accelerator hitting a thin target at a low incidence angle. The positrons are collected with a set of coils adapted to the large production angle. The collection system is designed to inject the positrons into a Greaves-Surko trap (Phys. Rev. A 46 (1992) 5696). Such a source could be the basis for a series of experiments in fundamental and applied research and would also be a prototype source for industrial applications, which concern the field of defect characterization in the nanometer scale.

The Upgrade of the Neutron Induced Positron Source NEPOMUC

NASA Astrophysics Data System (ADS)

Hugenschmidt, C.; Ceeh, H.; Gigl, T.; Lippert, F.; Piochacz, C.; Pikart, P.; Reiner, M.; Weber, J.; Zimnik, S.

2013-06-01

In summer 2012, the new NEutron induced POsitron Source MUniCh (NEPOMUC) was installed and put into operation at the research reactor FRM II. At NEPOMUC upgrade 80% 113Cd enriched Cd is used as neutron-gamma converter in order to ensure an operation time of 25 years. A structure of Pt foils inside the beam tube generates positrons by pair production. Moderated positrons leaving the Pt front foil are electrically extracted and magnetically guided to the outside of the reactor pool. The whole design, including Pt-foils, the electric lenses and the magnetic fields, has been improved in order to enhance both the intensity and the brightness of the positron beam. After adjusting the potentials and the magnetic guide and compensation fields an intensity of about 3·109 moderated positrons per second is expected. During the first start-up, the measured temperatures of about 90°C ensure a reliable operation of the positron source. Within this contribution the features and the status of NEPOMUC upgrade are elucidated. In addition, an overview of recent positron beam experiments and current developments at the spectrometers is given.

Development of mini linac-based positron source and an efficient positronium convertor for positively charged antihydrogen production

NASA Astrophysics Data System (ADS)

Muranaka, T.; Debu, P.; Dupré, P.; Liszkay, L.; Mansoulie, B.; Pérez, P.; Rey, J. M.; Ruiz, N.; Sacquin, Y.; Crivelli, P.; Gendotti, U.; Rubbia, A.

2010-04-01

We have installed in Saclay a facility for an intense positron source in November 2008. It is based on a compact 5.5 MeV electron linac connected to a reaction chamber with a tungsten target inside to produce positrons via pair production. The expected production rate for fast positrons is 5·1011 per second. The study of moderation of fast positrons and the construction of a slow positron trap are underway. In parallel, we have investigated an efficient positron-positronium convertor using porous silica materials. These studies are parts of a project to produce positively charged antihydrogen ions aiming to demonstrate the feasibility of a free fall antigravity measurement of neutral antihydrogen.

Chaos of energetic positron orbits in a dipole magnetic field and its potential application to a new injection scheme

NASA Astrophysics Data System (ADS)

Saitoh, H.; Yoshida, Z.; Yano, Y.; Nishiura, M.; Kawazura, Y.; Horn-Stanja, J.; Pedersen, T. Sunn

2016-10-01

We study the behavior of high-energy positrons emitted from a radioactive source in a magnetospheric dipole field configuration. Because the conservation of the first and second adiabatic invariants is easily destroyed in a strongly inhomogeneous dipole field for high-energy charged particles, the positron orbits are nonintegrable, resulting in chaotic motions. In the geometry of a typical magnetospheric levitated dipole experiment, it is shown that a considerable ratio of positrons from a 22Na source, located at the edge of the confinement region, has chaotic long orbit lengths before annihilation. These particles make multiple toroidal circulations and form a hollow toroidal positron cloud. Experiments with a small 22Na source in the Ring Trap 1 (RT-1) device demonstrated the existence of such long-lived positrons in a dipole field. Such a chaotic behavior of high-energy particles is potentially applicable to the formation of a dense toroidal positron cloud in the strong-field region of the dipole field in future studies.

Development of a Slow Positron Facility at Hebrew University of Jerusalem

NASA Astrophysics Data System (ADS)

Kelleher, Aidan

2013-03-01

Positron annihilation spectroscopy provides both depth of penetration to study bulk defects in materials as well as nano-scale resolution. This measurement range is achieved by slowing positrons from a radioactive source, typically 22Na, by sending them through a moderator, typically W or solid Ne. The nearly thermal positrons are then accelerated to the desired energy by means of an electrostatic potential. The SPOT project at The Hebrew University of Jerusalem proposes to increase the luminosity of the beam by applying the best practices currently in us, as well as using a short-lived source of positrons, 18F. Simulations based on our current designs indicate this project will be able to deliver positrons in the energy range of 50-50000eV with an energy resolution of 1eV is possible. We will present the unique technical challenges of using this source of positrons, how we plan to overcome them, the results of simulations, and facility construction progress.

Non-destructive testing method and apparatus

DOEpatents

Akers, Douglas W [Idaho Falls, ID

2011-10-04

Non-destructive testing apparatus may comprise a photon source and a source material that emits positrons in response to bombardment of the source material with photons. The source material is positionable adjacent the photon source and a specimen so that when the source material is positioned adjacent the photon source it is exposed to photons produced thereby. When the source material is positioned adjacent the specimen, the specimen is exposed to at least some of the positrons emitted by the source material. A detector system positioned adjacent the specimen detects annihilation gamma rays emitted by the specimen. Another embodiment comprises a neutron source and a source material that emits positrons in response to neutron bombardment.

Probing the positron moderation process using high-intensity, highly polarized slow-positron beams

NASA Technical Reports Server (NTRS)

Van House, J.; Zitzewitz, P. W.

1984-01-01

A highly polarized (P = 0.48 + or - 0.02) intense (500,000/sec) beam of 'slow' (Delta E = about 2 eV) positrons (e+) is generated, and it is shown that it is possible to achieve polarization as high as P = 0.69 + or - 0.04 with reduced intensity. The measured polarization of the slow e+ emitted by five different positron moderators showed no dependence on the moderator atomic number (Z). It is concluded that only source positrons with final kinetic energy below 17 keV contribute to the slow-e+ beam, in disagreement with recent yield functions derived from low-energy measurements. Measurements of polarization and yield with absorbers of different Z between the source and moderator show the effects of the energy and angular distributions of the source positrons on P. The depolarization of fast e+ transmitted through high-Z absorbers has been measured. Applications of polarized slow-e+ beams are discussed.

Diffuse Galactic antimatter from faint thermonuclear supernovae in old stellar populations

NASA Astrophysics Data System (ADS)

Crocker, Roland M.; Ruiter, Ashley J.; Seitenzahl, Ivo R.; Panther, Fiona H.; Sim, Stuart; Baumgardt, Holger; Möller, Anais; Nataf, David M.; Ferrario, Lilia; Eldridge, J. J.; White, Martin; Tucker, Brad E.; Aharonian, Felix

2017-06-01

Our Galaxy hosts the annihilation of a few 1043 low-energy positrons every second. Radioactive isotopes capable of supplying such positrons are synthesized in stars, stellar remnants and supernovae. For decades, however, there has been no positive identification of a main stellar positron source, leading to suggestions that many positrons originate from exotic sources like the Galaxy's central supermassive black hole or dark matter annihilation. Here we show that a single type of transient source, deriving from stellar populations of age 3-6 Gyr and yielding ∼0.03 M ⊙ of the positron emitter 44Ti, can simultaneously explain the strength and morphology of the Galactic positron annihilation signal and the Solar System abundance of the 44Ti decay product 44Ca. This transient is likely the merger of two low-mass white dwarfs, observed in external galaxies as the sub-luminous, thermonuclear supernova known as SN 1991bg-like.

Effect of the diffusion parameters on the observed γ-ray spectrum of sources and their contribution to the local all-electron spectrum: The EDGE code

NASA Astrophysics Data System (ADS)

López-Coto, R.; Hahn, J.; BenZvi, S.; Dingus, B.; Hinton, J.; Nisa, M. U.; Parsons, R. D.; Greus, F. Salesa; Zhang, H.; Zhou, H.

2018-11-01

The positron excess measured by PAMELA and AMS can only be explained if there is one or several sources injecting them. Moreover, at the highest energies, it requires the presence of nearby ( ∼ hundreds of parsecs) and middle age (maximum of ∼ hundreds of kyr) sources. Pulsars, as factories of electrons and positrons, are one of the proposed candidates to explain the origin of this excess. To calculate the contribution of these sources to the electron and positron flux at the Earth, we developed EDGE (Electron Diffusion and Gamma rays to the Earth), a code to treat the propagation of electrons and compute their diffusion from a central source with a flexible injection spectrum. Using this code, we can derive the source's gamma-ray spectrum, spatial extension, the all-electron density in space, the electron and positron flux reaching the Earth and the positron fraction measured at the Earth. We present in this paper the foundations of the code and study how different parameters affect the gamma-ray spectrum of a source and the electron flux measured at the Earth. We also studied the effect of several approximations usually performed in these studies. This code has been used to derive the results of the positron flux measured at the Earth in [1].

A positron remoderator for the high intensity positron source NEPOMUC

NASA Astrophysics Data System (ADS)

Piochacz, Christian; Kögel, Gottfried; Egger, Werner; Hugenschmidt, Christoph; Mayer, Jakob; Schreckenbach, Klaus; Sperr, Peter; Stadlbauer, Martin; Dollinger, Günther

2008-10-01

A remoderator for the high intensity positron source NEPOMUC was developed and installed at the beam facility. A beam of remoderated positrons could be produced with different energies and a diameter of less than 2 mm was obtained. The efficiency of the remoderation setup was determined to be 5%. Due to the brilliance of the remoderated beam, the measurements at the coincidence Doppler broadening spectrometer (CDBS) and at the positron annihilation induced Auger electron spectrometer (PAES) could be improved. The setup and functionality of the remoderation device is presented as well as the first measurements at the remoderator, CDBS and PAES.

Formation of a high intensity low energy positron string

NASA Astrophysics Data System (ADS)

Donets, E. D.; Donets, E. E.; Syresin, E. M.; Itahashi, T.; Dubinov, A. E.

2004-05-01

The possibility of a high intensity low energy positron beam production is discussed. The proposed Positron String Trap (PST) is based on the principles and technology of the Electron String Ion Source (ESIS) developed in JINR during the last decade. A linear version of ESIS has been used successfully for the production of intense highly charged ion beams of various elements. Now the Tubular Electron String Ion Source (TESIS) concept is under study and this opens really new promising possibilities in physics and technology. In this report, we discuss the application of the tubular-type trap for the storage of positrons cooled to the cryogenic temperatures of 0.05 meV. It is intended that the positron flux at the energy of 1-5 eV, produced by the external source, is injected into the Tubular Positron Trap which has a similar construction as the TESIS. Then the low energy positrons are captured in the PST Penning trap and are cooled down because of their synchrotron radiation in the strong (5-10 T) applied magnetic field. It is expected that the proposed PST should permit storing and cooling to cryogenic temperature of up to 5×109 positrons. The accumulated cooled positrons can be used further for various physics applications, for example, antihydrogen production.

Present status of the low energy linac-based slow positron beam and positronium spectrometer in Saclay

NASA Astrophysics Data System (ADS)

Liszkay, L.; Comini, P.; Corbel, C.; Debu, P.; Grandemange, P.; Pérez, P.; Rey, J.-M.; Reymond, J.-M.; Ruiz, N.; Sacquin, Y.; Vallage, B.

2014-04-01

A new slow positron beamline featuring a large acceptance positronium lifetime spectrometer has been constructed and tested at the linac-based slow positron source at IRFU CEA Saclay, France. The new instrument will be used in the development of a dense positronium target cloud for the GBAR experiment. The GBAR project aims at precise measurement of the gravitational acceleration of antihydrogen in the gravitational field of the Earth. Beyond application in fundamental science, the positron spectrometer will be used in materials research, for testing thin porous films and layers by means of positronium annihilation. The slow positron beamline is being used as a test bench to develop further instrumentation for positron annihilation spectroscopy (Ps time-of-flight, pulsed positron beam). The positron source is built on a low energy linear electron accelerator (linac). The 4.3 MeV electron energy used is well below the photoneutron threshold, making the source a genuine on-off device, without remaining radioactivity. The spectrometer features large BGO (Bismuth Germanate) scintillator detectors, with sufficiently large acceptance to detect all ortho-positronium annihilation lifetime components (annihilation in vacuum and in nanopores).

Polarized γ source based on Compton backscattering in a laser cavity

NASA Astrophysics Data System (ADS)

Yakimenko, V.; Pogorelsky, I. V.

2006-09-01

We propose a novel gamma source suitable for generating a polarized positron beam for the next generation of electron-positron colliders, such as the International Linear Collider (ILC), and the Compact Linear Collider (CLIC). This 30-MeV polarized gamma source is based on Compton scattering inside a picosecond CO2 laser cavity generated from electron bunches produced by a 4-GeV linac. We identified and experimentally verified the optimum conditions for obtaining at least one gamma photon per electron. After multiplication at several consecutive interaction points, the circularly polarized gamma rays are stopped on a target, thereby creating copious numbers of polarized positrons. We address the practicality of having an intracavity Compton-polarized positron source as the injector for these new colliders.

Synthesis and preclinical characterization of 1-(6'-deoxy-6'-[18F]fluoro-β-d-allofuranosyl)-2-nitroimidazole (β-6'-[18F]FAZAL) as a positron emission tomography radiotracer to assess tumor hypoxia.

PubMed

Wanek, Thomas; Kreis, Katharina; Križková, Petra; Schweifer, Anna; Denk, Christoph; Stanek, Johann; Mairinger, Severin; Filip, Thomas; Sauberer, Michael; Edelhofer, Patricia; Traxl, Alexander; Muchitsch, Viktoria E; Mereiter, Kurt; Hammerschmidt, Friedrich; Cass, Carol E; Damaraju, Vijaya L; Langer, Oliver; Kuntner, Claudia

2016-11-01

Positron emission tomography (PET) using fluorine-18 ( 18 F)-labeled 2-nitroimidazole radiotracers has proven useful for assessment of tumor oxygenation. However, the passive diffusion-driven cellular uptake of currently available radiotracers results in slow kinetics and low tumor-to-background ratios. With the aim to develop a compound that is actively transported into cells, 1-(6'-deoxy-6'-[ 18 F]fluoro-β-d-allofuranosyl)-2-nitroimidazole (β-[ 18 F]1), a putative nucleoside transporter substrate, was synthetized by nucleophilic [ 18 F]fluoride substitution of an acetyl protected labeling precursor with a tosylate leaving group (β-6) in a final radiochemical yield of 12±8% (n=10, based on [ 18 F]fluoride starting activity) in a total synthesis time of 60min with a specific activity at end of synthesis of 218±58GBq/μmol (n=10). Both radiolabeling precursor β-6 and unlabeled reference compound β-1 were prepared in multistep syntheses starting from 1,2:5,6-di-O-isopropylidene-α-d-allofuranose. In vitro experiments demonstrated an interaction of β-1 with SLC29A1 and SLC28A1/2/3 nucleoside transporter as well as hypoxia specific retention of β-[ 18 F]1 in tumor cell lines. In biodistribution studies in healthy mice β-[ 18 F]1 showed homogenous tissue distribution and excellent metabolic stability, which was unaffected by tissue oxygenation. PET studies in tumor bearing mice showed tumor-to-muscle ratios of 2.13±0.22 (n=4) at 2h after administration of β-[ 18 F]1. In ex vivo autoradiography experiments β-[ 18 F]1 distribution closely matched staining with the hypoxia marker pimonidazole. In conclusion, β-[ 18 F]1 shows potential as PET hypoxia radiotracer which merits further investigation. Copyright © 2016 Elsevier Ltd. All rights reserved.

A Central Positron Source to Perform the Timing Alignment of Detectors in a PET Scanner

NASA Astrophysics Data System (ADS)

Thompson, C. J.; Camborde, M.-L.; Casey, M. E.

2005-10-01

Accurate timing alignment and stability are important to maximize the true counts and minimize the random counts in positron emission tomography. Its importance increases in time-of-flight (TOF) scanners. We propose using a central positron emitting source enclosed in a detector which detects the excess energy of the positron before it annihilates as a timing reference. All crystals can be time-aligned with respect to this central source. We evaluated 10 /spl mu/Ci /sup 22/Na and /sup 68/Ge sources embedded in cylinders of plastic scintillator coupled to a fast PMT. Light flashes produced after the parent isotope emits positrons are detected, and the anode signals from the PMT are the reference time for each positron decay. The time delay before the gamma ray is detected by the scanner's conventional gamma ray detectors is the time offset to be applied to that crystal. Since all detectors are almost the same distance from the central source, TOF errors are minimized. Preliminary results show a mean signal amplitude of >0.5 V from /sup 22/Na at 1000-V PMT bias, a timing FWHM of 850 ps with respect to a small LSO crystal. This suggests it could be useful to align both conventional and TOF PET scanners.

A self-consistent model of cosmic-ray fluxes and positron excess: roles of nearby pulsars and a sub-dominant source population

NASA Astrophysics Data System (ADS)

Joshi, Jagdish C.; Razzaque, Soebur

2017-09-01

The cosmic-ray positron flux calculated using the cosmic-ray nuclei interactions in our Galaxy cannot explain observed data above 10 GeV. An excess in the measured positron flux is therefore open to interpretation. Nearby pulsars, located within sub-kiloparsec range of the Solar system, are often invoked as plausible sources contributing to the excess. We show that an additional, sub-dominant population of sources together with the contributions from a few nearby pulsars can explain the latest positron excess data from the Alpha Magnetic Spectrometer (AMS). We simultaneously model, using the DRAGON code, propagation of cosmic-ray proton, Helium, electron and positron and fit their respective flux data. Our fit to the Boron to Carbon ratio data gives a diffusion spectral index of 0.45, which is close to the Kraichnan turbulent spectrum.

A self-consistent model of cosmic-ray fluxes and positron excess: roles of nearby pulsars and a sub-dominant source population

DOE Office of Scientific and Technical Information (OSTI.GOV)

Joshi, Jagdish C.; Razzaque, Soebur, E-mail: jjagdish@uj.ac.za, E-mail: srazzaque@uj.ac.za

The cosmic-ray positron flux calculated using the cosmic-ray nuclei interactions in our Galaxy cannot explain observed data above 10 GeV. An excess in the measured positron flux is therefore open to interpretation. Nearby pulsars, located within sub-kiloparsec range of the Solar system, are often invoked as plausible sources contributing to the excess. We show that an additional, sub-dominant population of sources together with the contributions from a few nearby pulsars can explain the latest positron excess data from the Alpha Magnetic Spectrometer (AMS). We simultaneously model, using the DRAGON code, propagation of cosmic-ray proton, Helium, electron and positron and fitmore » their respective flux data. Our fit to the Boron to Carbon ratio data gives a diffusion spectral index of 0.45, which is close to the Kraichnan turbulent spectrum.« less

Texas Intense Positron Source (TIPS)

NASA Astrophysics Data System (ADS)

O'Kelly, D.

2003-03-01

The Texas Intense Positron Source (TIPS) is a state of the art variable energy positron beam under construction at the Nuclear Engineering Teaching Laboratory (NETL). Projected intensities on the order of the order of 10^7 e+/second using ^64Cu as the positron source are expected. Owing to is short half-life (t1/2 12.8 hrs), plans are to produce the ^64Cu isotope on-site using beam port 1 of NETL TRIGA Mark II reactor. Following tungsten moderation, the positrons will be electrostatically focused and accelerated from few 10's of eV up to 30 keV. This intensity and energy range should allow routine performance of several analytical techniques of interest to surface scientists (PALS, PADB and perhaps PAES and LEPD.) The TIPS project is being developed in parallel phases. Phase I of the project entails construction of the vacuum system, source chamber, main beam line, electrostatic/magnetic focusing and transport system as well as moderator design. Initial construction, testing and characterization of moderator and beam transport elements are underway and will use a commercially available 10 mCi ^22Na radioisotope as a source of positrons. Phase II of the project is concerned primarily with the Cu source geometry and thermal properties as well as production and physical handling of the radioisotope. Additional instrument optimizing based upon experience gained during Phase I will be incorporated in the final design. Current progress of both phases will be presented along with motivations and future directions.

Method for non-destructive testing

DOEpatents

Akers, Douglas W [Idaho Falls, ID

2011-08-30

Non-destructive testing method may include providing a source material that emits positrons in response to bombardment of the source material with photons. The source material is exposed to photons. The source material is positioned adjacent the specimen, the specimen being exposed to at least some of the positrons emitted by the source material. Annihilation gamma rays emitted by the specimen are detected.

Method for on-line evaluation of materials using prompt gamma ray analysis

DOEpatents

Akers, Douglas W [Idaho Falls, ID

2009-12-08

A method for evaluating a material specimen comprises: Mounting a neutron source and a detector adjacent the material specimen; bombarding the material specimen with neutrons from the neutron source to create prompt gamma rays within the material specimen, some of the prompt gamma rays being emitted from the material specimen, some of the prompt gamma rays resulting in the formation of positrons within the material specimen by pair production; collecting positron annihilation data by detecting with the detector at least one emitted annihilation gamma ray resulting from the annihilation of a positron; storing the positron annihilation data on a data storage system for later retrieval and processing; and continuing to collect and store positron annihilation data, the continued collected and stored positron annihilation data being indicative of an accumulation of lattice damage over time.

Apparatus for photon activation positron annihilation analysis

DOEpatents

Akers, Douglas W [Idaho Falls, ID

2007-06-12

Non-destructive testing apparatus according to one embodiment of the invention comprises a photon source. The photon source produces photons having predetermined energies and directs the photons toward a specimen being tested. The photons from the photon source result in the creation of positrons within the specimen being tested. A detector positioned adjacent the specimen being tested detects gamma rays produced by annihilation of positrons with electrons. A data processing system operatively associated with the detector produces output data indicative of a lattice characteristic of the specimen being tested.

Is There a Dark Matter Signal in the Galactic Positron Annihilation Radiation?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lingenfelter, R. E.; Rothschild, R. E.; Higdon, J. C.

2009-07-17

Assuming Galactic positrons do not go far before annihilating, a difference between the observed 511 keV annihilation flux distribution and that of positron production, expected from beta{sup +} decay in Galactic iron nucleosynthesis, was evoked as evidence of a new source and signal of dark matter. We show, however, that the dark matter sources cannot account for the observed positronium fraction without extensive propagation. Yet with such propagation, standard nucleosynthetic sources can fully account for the spatial differences and positronium fraction, leaving no new signal for dark matter to explain.

Positron source position sensing detector and electronics

DOEpatents

Burnham, Charles A.; Bradshaw, Jr., John F.; Kaufman, David E.; Chesler, David A.; Brownell, Gordon L.

1985-01-01

A positron source, position sensing device, particularly with medical applications, in which positron induced gamma radiation is detected using a ring of stacked, individual scintillation crystals, a plurality of photodetectors, separated from the scintillation crystals by a light guide, and high resolution position interpolation electronics. Preferably the scintillation crystals are several times more numerous than the photodetectors with each crystal being responsible for a single scintillation event from a received gamma ray. The light guide will disperse the light emitted from gamma ray absorption over several photodetectors. Processing electronics for the output of the photodetectors resolves the location of the scintillation event to a fraction of the dimension of each photodetector. Because each positron absorption results in two 180.degree. oppositely traveling gamma rays, the detection of scintillation in pairs permits location of the positron source in a manner useful for diagnostic purposes. The processing electronics simultaneously responds to the outputs of the photodetectors to locate the scintillations to the source crystal. While it is preferable that the scintillation crystal include a plurality of stacked crystal elements, the resolving power of the processing electronics is also applicable to continuous crystal scintillators.

Positron annihilation lifetime spectroscopy study of Kapton thin foils

NASA Astrophysics Data System (ADS)

Kanda, G. S.; Ravelli, L.; Löwe, B.; Egger, W.; Keeble, D. J.

2016-01-01

Variable energy positron annihilation lifetime spectroscopy (VE-PALS) experiments on polyimide material Kapton are reported. Thin Kapton foils are widely used in a variety of mechanical, electronic applications. PALS provides a sensitive probe of vacancy-related defects in a wide range of materials, including open volume in polymers. Varying the positron implantation energy enables direct measurement of thin foils. Thin Kapton foils are also commonly used to enclose the positron source material in conventional PALS measurements performed with unmoderated radionuclide sources. The results of depth-profiled positron lifetime measurements on 7.6 μm and 25 μm Kapton foils are reported and determine a dominant 385(1) ps lifetime component. The absence of significant nanosecond lifetime component due to positronium formation is confirmed.

Positron radiography of ignition-relevant ICF capsules

NASA Astrophysics Data System (ADS)

Williams, G. J.; Chen, Hui; Field, J. E.; Landen, O. L.; Strozzi, D. J.

2017-12-01

Laser-generated positrons are evaluated as a probe source to radiograph in-flight ignition-relevant inertial confinement fusion capsules. Current ultraintense laser facilities are capable of producing 2 × 1012 relativistic positrons in a narrow energy bandwidth and short time duration. Monte Carlo simulations suggest that the unique characteristics of such positrons allow for the reconstruction of both capsule shell radius and areal density between 0.002 and 2 g/cm2. The energy-downshifted positron spectrum and angular scattering of the source particles are sufficient to constrain the conditions of the capsule between preshot and stagnation. We evaluate the effects of magnetic fields near the capsule surface using analytic estimates where it is shown that this diagnostic can tolerate line integrated field strengths of 100 T mm.

Microstructural probing of ferritic/martensitic steels using internal transmutation-based positron source

NASA Astrophysics Data System (ADS)

Krsjak, Vladimir; Dai, Yong

2015-10-01

This paper presents the use of an internal 44Ti/44Sc radioisotope source for a direct microstructural characterization of ferritic/martensitic (f/m) steels after irradiation in targets of spallation neutron sources. Gamma spectroscopy measurements show a production of ∼1MBq of 44Ti per 1 g of f/m steels irradiated at 1 dpa (displaced per atom) in the mixed proton-neutron spectrum at the Swiss spallation neutron source (SINQ). In the decay chain 44Ti → 44Sc → 44Ca, positrons are produced together with prompt gamma rays which enable the application of different positron annihilation spectroscopy (PAS) analyses, including lifetime and Doppler broadening spectroscopy. Due to the high production yield, long half-life and relatively high energy of positrons of 44Ti, this methodology opens up new potential for simple, effective and inexpensive characterization of radiation induced defects in f/m steels irradiated in a spallation target.

Stable confinement of electron plasma and initial results on positron injection in RT-1

NASA Astrophysics Data System (ADS)

Saitoh, H.; Yoshida, Z.; Morikawa, J.; Yano, Y.; Kasaoka, N.; Sakamoto, W.; Nogami, T.

2013-03-01

The Ring Trap 1 (RT-1) device is a dipole field configuration generated by a levitated superconducting magnet. It offers very interesting opportunities for research on the fundamental properties on non-neutral plasmas, such as self-organization of charged particles in the strongly positive and negative charged particles on magnetic surfaces. When strong positron sources will be available in the future, the dipole field configuration will be potentially applicable to the formation of an electron-positron plasma. We have realized stable, long trap of toroidal pure electron plasma in RT-1; Magnetic levitation of the superconducting magnet resulted in more than 300s of confinement for electron plasma of ˜ 1011 m-3. Aiming for the confinement of positrons as a next step, we started a positron injection experiment. For the formation of positron plasma in the closed magnetic surfaces, one of the key issues to be solved is the efficient injection method of positron across closed magnetic surfaces. In contrast to linear configurations, toroidal configurations have the advantage that they are capable of trapping high energy positrons in the dipole field configuration and consider the possibility of direct trapping of positrons emitted from a 22Na source.

Monte Carlo investigation of positron annihilation in medical positron emission tomography

NASA Astrophysics Data System (ADS)

Chin, P. W.; Spyrou, N. M.

2007-09-01

A number of Monte Carlo codes are available for simulating positron emission tomography (PET), however, physics approximations differ. A number of radiation processes are deemed negligible, some without rigorous investigation. Some PET literature quantify approximations to be valid, without citing the data source. The radiation source is the first step in Monte Carlo simulations, for some codes this is 511 keV photons 180° apart, not polyenergetic positrons with radiation histories of their own. Without prior assumptions, we investigated electron-positron annihilation under clinical PET conditions. Just before annihilation, we tallied the positron energy and position. Right after annihilation, we tallied the energy and separation angle of photon pairs. When comparing PET textbooks with theory, PENELOPE and EGSnrc, only the latter three agreed. From 10 6 radiation histories, a positron source of 15O in a chest phantom annihilated at as high as 1.58 MeV, producing photons with energies 0.30-2.20 MeV, 79-180° apart. From 10 6 radiation histories, an 18F positron source in a head phantom annihilated at energies as high as 0.56 MeV, producing 0.33-1.18 MeV photons 109-180° apart. 2.5% and 0.8% annihilation events occurred inflight in the chest and the head phantoms, respectively. PET textbooks typically either do not mention any deviation from 180°, or state a deviation of 0.25° or 0.5°. Our findings are founded on the well-established Heitler cross-sections and relativistic kinematics, both adopted unanimously by PENELOPE, EGSnrc and GEANT4. Our results highlight the effects of annihilation in-flight, a process sometimes forgotten within the PET community.

Construction of the Helsinki University of Technology (HUT) pulsed positron beam

NASA Astrophysics Data System (ADS)

Fallström, K.; Laine, T.

1999-08-01

We are constructing a pulsed positron beam facility for lifetime measurements in thin surface layers. Our beam system comprises a 22Na positron source and a tungsten foil moderator followed by a prebuncher and a chopper. A double-drift buncher will compress the beam into 120-ps pulses at the target. The end energy of the positron beam can be adjusted between 3 keV and 30 keV by changing the potential of the source end of the beam. The bunching electronics and most of the beam guiding magnets are also floating at the high voltage. The sample is at ground potential to facilitate variable temperature measurements. With a test source of 6 mCi 22Na we get a prebunched beam intensity of 4×10 3 positrons per second in 1.5-ns wide pulses (the bunching frequency is 33.33 MHz). We are currently testing the chopper and the following buncher stages and building the final accelerator/decelerator system.

Positron radiography of ignition-relevant ICF capsules

DOE PAGES

Williams, G. J.; Chen, Hui; Field, J. E.; ...

2017-12-11

Laser-generated positrons are evaluated as a probe source to radiograph in-flight ignition-relevant inertial confinement fusion capsules. Current ultraintense laser facilities are capable of producing 2 ×10 12 relativistic positrons in a narrow energy bandwidth and short time duration. Monte Carlo simulations suggest that the unique characteristics of such positrons allow for the reconstruction of both capsule shell radius and areal density between 0.002 and 2g/cm 2. The energy-downshifted positron spectrum and angular scattering of the source particles are sufficient to constrain the conditions of the capsule between preshot and stagnation. Here, we evaluate the effects of magnetic fields near themore » capsule surface using analytic estimates where it is shown that this diagnostic can tolerate line integrated field strengths of 100 T mm.« less

Positron radiography of ignition-relevant ICF capsules

DOE Office of Scientific and Technical Information (OSTI.GOV)

Williams, G. J.; Chen, Hui; Field, J. E.

Laser-generated positrons are evaluated as a probe source to radiograph in-flight ignition-relevant inertial confinement fusion capsules. Current ultraintense laser facilities are capable of producing 2 ×10 12 relativistic positrons in a narrow energy bandwidth and short time duration. Monte Carlo simulations suggest that the unique characteristics of such positrons allow for the reconstruction of both capsule shell radius and areal density between 0.002 and 2g/cm 2. The energy-downshifted positron spectrum and angular scattering of the source particles are sufficient to constrain the conditions of the capsule between preshot and stagnation. Here, we evaluate the effects of magnetic fields near themore » capsule surface using analytic estimates where it is shown that this diagnostic can tolerate line integrated field strengths of 100 T mm.« less

Choline transporter-like proteins CTLs/SLC44 family as a novel molecular target for cancer therapy.

PubMed

Inazu, Masato

2014-11-01

Choline is essential for the synthesis of the major membrane phospholipid phosphatidylcholine (PC), the methyl donor betaine and the neurotransmitter acetylcholine (ACh). Elevated levels of choline and up-regulated choline kinase activity have been detected in various cancers. Thus, the intracellular accumulation of choline through choline transporters is the rate-limiting step in phospholipid metabolism and a prerequisite for cancer cell proliferation. Previous studies have demonstrated abnormalities in choline uptake and choline phospholipid metabolism in cancer cells using the imaging of cancer with positron emission tomography (PET) and magnetic resonance spectroscopy (MRS). The aberrant choline metabolism in cancer cells is strongly correlated with their malignant progression. Using quantitative real-time PCR, the mRNA expression of choline transporters was measured, and it was found that choline transporter-like proteins CTLs/SLC44 family are highly expressed in various cancer cell lines. Choline uptake through CTLs is associated with cell viability, and the functional inhibition of CTLs could promote apoptotic cell death. Furthermore, non-neuronal cholinergic systems that include CTLs-mediated choline transport are associated with cell proliferation and their inhibition promotes apoptotic cell death in colon cancer, small cell lung cancer and human leukemic T-cells. The identification of this new CTLs-mediated choline transport system provides a potential new target for cancer therapy. Copyright © 2014 John Wiley & Sons, Ltd.

Solute Carriers in the Blood-Brain Barier: Safety in Abundance.

PubMed

Nałęcz, Katarzyna A

2017-03-01

Blood-brain barrier formed by brain capillary endothelial cells, being in contact with astrocytes endfeet and pericytes, separates extracellular fluid from plasma. Supply of necessary nutrients and removal of certain metabolites takes place due to the activity of transporting proteins from ABC (ATP binding cassette) and SLC (solute carrier) superfamilies. This review is focused on the SLC families involved in transport though the blood-brain barrier of energetic substrates (glucose, monocarboxylates, creatine), amino acids, neurotransmitters and their precursors, as well as organic ions. Members of SLC1, SLC2, SLC3/SLC7, SLC5, SLC6, SLC16, SLC22, SLC38, SLC44, SLC47 and SLCO (SLC21), whose presence in the blood-brain barriers has been demonstrated are characterized with a special emphasis put on polarity of transporters localization in a luminal (blood side) versus an abluminal (brain side) membrane.

Evaluation of Landsat-7 SLC-off image products for forest change detection

USGS Publications Warehouse

Wulder, Michael A.; Ortlepp, Stephanie M.; White, Joanne C.; Maxwell, Susan

2008-01-01

Since July 2003, Landsat-7 ETM+ has been operating without the scan line corrector (SLC), which compensates for the forward motion of the satellite in the imagery acquired. Data collected in SLC-off mode have gaps in a systematic wedge-shaped pattern outside of the central 22 km swath of the imagery; however, the spatial and spectral quality of the remaining portions of the imagery are not diminished. To explore the continued use of Landsat-7 ETM+ SLC-off imagery to characterize change in forested environments, we compare the change detection results generated from a reference image pair (a 1999 Landsat-7 ETM+ image and a 2003 Landsat-5 TM image) with change detection results generated from the same 1999 Landsat-7 ETM+ image coupled with three different 2003 Landsat-7 SLC-off products: unremediated SLC-off (i.e., with gaps); histogram-based gap-filled; and segment-based gap-filled. The results are compared on both a pixel and polygon basis; on a pixel basis, the unremediated SLC-off product missed 35% of the change identified by the reference data, and the histogram- and segment-based gap-filled products missed 23% and 21% of the change, respectively. When using forest inventory polygons as a context for change (to reduce commission error), the amount of change missed was 31%, 14%, and 12% for the each of the unremediated, histogram-based gap-filled, and segment-based gap-filled products, respectively. Our results indicate that over the time period considered, and given the types and spatial distribution of change events within our study area, the gap-filled products can provide a useful data source for change detection in forested environments. The selection of which product to use is, however, very dependent on the nature of the application and the spatial configuration of change events. ?? 2008 Government of Canada.

The solute carrier family 10 (SLC10): beyond bile acid transport

PubMed Central

da Silva, Tatiana Claro; Polli, James E.; Swaan, Peter W.

2012-01-01

The solute carrier (SLC) family 10 (SLC10) comprises influx transporters of bile acids, steroidal hormones, various drugs, and several other substrates. Because the seminal transporters of this family, namely, sodium/taurocholate cotransporting polypeptide (NTCP; SLC10A1) and the apical sodium-dependent bile acid transporter (ASBT; SLC10A2), were primarily bile acid transporters, the term “sodium bile salt cotransporting family” was used for the SLC10 family. However, this notion became obsolete with the finding of other SLC10 members that do not transport bile acids. For example, the sodium-dependent organic anion transporter (SOAT; SLC10A6) transports primarily sulfated steroids. Moreover, NTCP was shown to also transport steroids and xenobiotics, including HMG-CoA inhibitors (statins). The SLC10 family contains four additional members, namely, P3 (SLC10A3; SLC10A3), P4 (SLC10A4; SLC10A4), P5 (SLC10A5; SLC10A5) and SLC10A7 (SLC10A7), several of which were unknown or considered hypothetical until approximately a decade ago. While their substrate specificity remains undetermined, great progress has been made towards their characterization in recent years. SLC10A4 may participate in vesicular storage or exocytosis of neurotransmitters or mastocyte mediators, whereas SLC10A5 and SLC10A7 may be involved in solute transport and SLC10A3 may have a role as a housekeeping protein. Finally, the newly found role of bile acids in glucose and energy homeostasis, via the TGR5 receptor, sheds new light on the clinical relevance of ASBT and NTCP. The present mini-review provides a brief summary of recent progress on members of the SLC10 family. PMID:23506869

Radio frequency elevator for a pulsed positron beam

NASA Astrophysics Data System (ADS)

Dickmann, Marcel; Mitteneder, Johannes; Kögel, Gottfried; Egger, Werner; Sperr, Peter; Ackermann, Ulrich; Piochacz, Christian; Dollinger, Günther

2016-06-01

An elevator increases the potential energy of a particle beam with respect to ground potential without any alteration of kinetic energy and other beam parameters. This elevator is necessary for the implementation of the Munich Scanning Positron Microscope (SPM) at the intense positron source NEPOMUC at the research reactor FRM II in Munich. The principles of the rf elevator for pure electrostatically guided positrons are described. Measurements of beam quality behind the elevator are reported, which confirm that after the implementation of elevator and SPM at NEPOMUC the SPM can be operated at a considerably improved resolution (~ 0.3 μm) and event rate (~3.7 kHz) compared to the laboratory based β+-source.

Transport via SLC5A8 with Subsequent Inhibition of Histone Deacetylases HDAC1 and HDAC3 Underlies the Antitumor Activity of 3-Bromopyruvate

PubMed Central

Thangaraju, Muthusamy; Karunakaran, Senthil K.; Itagaki, Shiro; Gopal, Elangovan; Elangovan, Selvakumar; Prasad, Puttur D.; Ganapathy, Vadivel

2009-01-01

Background 3-Bromopyruvate is an alkylating agent with antitumor activity. It is currently believed that blockade of ATP production from glycolysis and mitochondria is the primary mechanism responsible for this antitumor effect. The present studies have uncovered a new and novel mechanism for the antitumor activity of 3-bromopyruvate. Methods Transport of 3-bromopyruvate via SLC5A8, a tumor suppressor and a Na+-coupled electrogenic transporter for short-chain monocarboxylates, was studied using a mammalian cell expression and the Xenopus laevis oocyte expression systems. The effect of 3-bromopyruvate on histone deacetylases (HDACs) was monitored using the lysate of the human breast cancer cell line MCF7 and human recombinant HDAC isoforms as the enzyme sources. Cell viability was monitored by FACS analysis and colony formation assay. Acetylation status of histone H4 was evaluated by Western blot. Results 3-Bromopyruvate is a transportable substrate for SLC5A8, with the transport process being Na+-coupled and electrogenic. MCF7 cells do not express SLC5A8 and are not affected by 3-bromopyruvate. However, when transfected with SLC5A8 or treated with inhibitors of DNA methylation, these cells undergo apoptosis in the presence of 3-bromopyruvate. This cell death is associated with inhibition of HDAC1/HDAC3. Studies with different isoforms of human recombinant HDACs identify HDAC1 and HDAC3 as the targets for 3-bromopyruvate. Conclusions 3-Bromopyruvate is transported into cells actively via the tumor suppressor SLC5A8 and the process is energized by an electrochemical Na+ gradient. Ectopic expression of the transporter in MCF7 cells leads to apoptosis, and the mechanism involves inhibition of HDAC1/HDAC3. PMID:19637353

Nutritional Stress Induced by Amino Acid Starvation Results in Changes for Slc38 Transporters in Immortalized Hypothalamic Neuronal Cells and Primary Cortex Cells.

PubMed

Hellsten, Sofie V; Tripathi, Rekha; Ceder, Mikaela M; Fredriksson, Robert

2018-01-01

Amino acid sensing and signaling is vital for cells, and both gene expression and protein levels of amino acid transporters are regulated in response to amino acid availability. Here, the aim was to study the regulation of all members of the SLC38 amino acid transporter family, Slc38a1-11 , in mouse brain cells following amino acid starvation. We reanalyzed microarray data for the immortalized hypothalamic cell line N25/2 subjected to complete amino acid starvation for 1, 2, 3, 5, or 16 h, focusing specifically on the SLC38 family. All 11 Slc38 genes were expressed in the cell line, and Slc38a1, Slc38a2 , and Slc38a7 were significantly upregulated at 5 h and most strongly at 16 h. Here, protein level changes were measured for SLC38A7 and the orphan family member SLC38A11 which has not been studied under different amino acid starvation condition at protein level. At 5 h, no significant alteration on protein level for either SLC38A7 or SLC38A11 could be detected. In addition, primary embryonic cortex cells were deprived of nine amino acids, the most common amino acids transported by the SLC38 family members, for 3 h, 7 h or 12 h, and the gene expression was measured using qPCR. Slc38a1, Slc38a2, Slc38a5, Slc38a6, Slc38a9 , and Slc38a10 were upregulated, while Slc38a3 and Slc38a7 were downregulated. Slc38a8 was upregulated at 5 h and downregulated at 12 h. In conclusion, several members from the SLC38 family are regulated depending on amino acid levels and are likely to be involved in amino acid sensing and signaling in brain.

Individualizing Treatment Approaches for Epileptic Patients with Glucose Transporter Type1 (GLUT-1) Deficiency

PubMed Central

Bozalija, Adnan; Jashari, Fisnik; Krasniqi, Shaip

2018-01-01

Monogenic and polygenic mutations are important contributors in patients suffering from epilepsy, including metabolic epilepsies which are inborn errors of metabolism with a good respond to specific dietetic treatments. Heterozygous variation in solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1) and mutations of the GLUT1/SLC2A2 gene results in the failure of glucose transport, which is related with a glucose type-1 transporter (GLUT1) deficiency syndrome (GLUT1DS). GLUT1 deficiency syndrome is a treatable disorder of glucose transport into the brain caused by a variety of mutations in the SLC2A1 gene which are the cause of different neurological disorders also with different types of epilepsy and related clinical phenotypes. Since patients continue to experience seizures due to a pharmacoresistance, an early clinical diagnosis associated with specific genetic testing in SLC2A1 pathogenic variants in clinical phenotypes could predict pure drug response and might improve safety and efficacy of treatment with the initiation of an alternative energy source including ketogenic or analog diets in such patients providing individualized strategy approaches. PMID:29303961

The status of the positron beam facility at NEPOMUC

NASA Astrophysics Data System (ADS)

Hugenschmidt, C.

2011-01-01

The NEutron induced POsitron source MUniCh NEPOMUC provides a high intensity positron beam with 9·108 moderated positrons per second with a primary beam energy of 1keV. After remoderation, the positron beam is magnetically guided to five experimental setups: a coincident Doppler-broadening spectrometer (CDBS), a positron annihilation induced Auger-electron spectrometer (PAES), a pulsed low-energy positron system (PLEPS) as well as an interface for providing a pulsed beam with further improved brightness. An apparatus for the production of the negatively charged positronium ion Ps- is currently in operation at the open multi-purpose beam port, where additional experiments can be realized. Within this contribution, an overview of the positron beam facility NEPOMUC with its instrumentation at the research reactor FRMII is given.

Extended gamma-ray sources around pulsars constrain the origin of the positron flux at Earth

NASA Astrophysics Data System (ADS)

Abeysekara, A. U.; Albert, A.; Alfaro, R.; Alvarez, C.; Álvarez, J. D.; Arceo, R.; Arteaga-Velázquez, J. C.; Avila Rojas, D.; Ayala Solares, H. A.; Barber, A. S.; Bautista-Elivar, N.; Becerril, A.; Belmont-Moreno, E.; BenZvi, S. Y.; Berley, D.; Bernal, A.; Braun, J.; Brisbois, C.; Caballero-Mora, K. S.; Capistrán, T.; Carramiñana, A.; Casanova, S.; Castillo, M.; Cotti, U.; Cotzomi, J.; Coutiño de León, S.; De León, C.; De la Fuente, E.; Dingus, B. L.; DuVernois, M. A.; Díaz-Vélez, J. C.; Ellsworth, R. W.; Engel, K.; Enríquez-Rivera, O.; Fiorino, D. W.; Fraija, N.; García-González, J. A.; Garfias, F.; Gerhardt, M.; González Muñoz, A.; González, M. M.; Goodman, J. A.; Hampel-Arias, Z.; Harding, J. P.; Hernández, S.; Hernández-Almada, A.; Hinton, J.; Hona, B.; Hui, C. M.; Hüntemeyer, P.; Iriarte, A.; Jardin-Blicq, A.; Joshi, V.; Kaufmann, S.; Kieda, D.; Lara, A.; Lauer, R. J.; Lee, W. H.; Lennarz, D.; Vargas, H. León; Linnemann, J. T.; Longinotti, A. L.; Luis Raya, G.; Luna-García, R.; López-Coto, R.; Malone, K.; Marinelli, S. S.; Martinez, O.; Martinez-Castellanos, I.; Martínez-Castro, J.; Martínez-Huerta, H.; Matthews, J. A.; Miranda-Romagnoli, P.; Moreno, E.; Mostafá, M.; Nellen, L.; Newbold, M.; Nisa, M. U.; Noriega-Papaqui, R.; Pelayo, R.; Pretz, J.; Pérez-Pérez, E. G.; Ren, Z.; Rho, C. D.; Rivière, C.; Rosa-González, D.; Rosenberg, M.; Ruiz-Velasco, E.; Salazar, H.; Salesa Greus, F.; Sandoval, A.; Schneider, M.; Schoorlemmer, H.; Sinnis, G.; Smith, A. J.; Springer, R. W.; Surajbali, P.; Taboada, I.; Tibolla, O.; Tollefson, K.; Torres, I.; Ukwatta, T. N.; Vianello, G.; Weisgarber, T.; Westerhoff, S.; Wisher, I. G.; Wood, J.; Yapici, T.; Yodh, G.; Younk, P. W.; Zepeda, A.; Zhou, H.; Guo, F.; Hahn, J.; Li, H.; Zhang, H.

2017-11-01

The unexpectedly high flux of cosmic-ray positrons detected at Earth may originate from nearby astrophysical sources, dark matter, or unknown processes of cosmic-ray secondary production. We report the detection, using the High-Altitude Water Cherenkov Observatory (HAWC), of extended tera–electron volt gamma-ray emission coincident with the locations of two nearby middle-aged pulsars (Geminga and PSR B0656+14). The HAWC observations demonstrate that these pulsars are indeed local sources of accelerated leptons, but the measured tera–electron volt emission profile constrains the diffusion of particles away from these sources to be much slower than previously assumed. We demonstrate that the leptons emitted by these objects are therefore unlikely to be the origin of the excess positrons, which may have a more exotic origin.

Development of slow positron beam lines and applications

NASA Astrophysics Data System (ADS)

Mondal, Nagendra Nath

2018-05-01

A positron is an antiparticle of an electron that can be formed in diverse methods: natural or artificial β-decay process, fission and fusion reactions, and a pair production of electron-positron occurred in the reactor and the high energy accelerator centers. Usually a long-lifetime radio isotope is customized for the construction of a slow positron beam lines in many laboratories. The typical intensity of this beam depends upon the strength of the positron source, moderator efficiency, and guiding, pulsing, focusing and detecting systems. This article will review a few positron beam lines and their potential applications in research, especially in the Positronium Bose-Einstein Condensation.

Estimate of S-values for children due to six positron emitting radionuclides used in PET examinations

NASA Astrophysics Data System (ADS)

Belinato, Walmir; Santos, William S.; Perini, Ana P.; Neves, Lucio P.; Caldas, Linda V. E.; Souza, Divanizia N.

2017-11-01

Positron emission tomography (PET) has revolutionized the diagnosis of cancer since its conception. When combined with computed tomography (CT), PET/CT performed in children produces highly accurate diagnoses from images of regions affected by malignant tumors. Considering the high risk to children when exposed to ionizing radiation, a dosimetric study for PET/CT procedures is necessary. Specific absorbed fractions (SAF) were determined for monoenergetic photons and positrons, as well as the S-values for six positron emitting radionuclides (11C, 13N, 18F, 68Ga, 82Rb, 15O), and 22 source organs. The study was performed for six pediatric anthropomorphic hybrid models, including the newborn and 1 year hermaphrodite, 5 and 10-year-old male and female, using the Monte Carlo N-Particle eXtended code (MCNPX, version 2.7.0). The results of the SAF in source organs and S-values for all organs showed to be inversely related to the age of the phantoms, which includes the variation of body weight. The results also showed that radionuclides with higher energy peak emission produces larger auto absorbed S-values due to local dose deposition by positron decay. The S-values for the source organs are considerably larger due to the interaction of tissue with non-penetrating particles (electrons and positrons) and present a linear relationship with the phantom body masses. The results of the S-values determined for positron-emitting radionuclides can be used to assess the radiation dose delivered to pediatric patients subjected to PET examination in clinical settings. The novelty of this work is associated with the determination of auto absorbed S-values, in six new pediatric virtual anthropomorphic phantoms, for six emitting positrons, commonly employed in PET exams.

Spatial and Temporal Variations of EC and OC Aerosol Combustion Sources in a Polluted Metropolitan Area

NASA Astrophysics Data System (ADS)

Mouteva, G.; Randerson, J. T.; Fahrni, S.; Santos, G.; Bush, S. E.; Ehleringer, J. R.; Czimczik, C. I.

2015-12-01

Anthropogenic emissions of carbonaceous aerosols are a major component of fine air particulate matter (PM2.5) in polluted metropolitan areas and in the global atmosphere. Elemental (EC) and organic carbon (OC) aerosols influence Earth's energy balance by means of direct and indirect pathways and EC has been suggested as a better indicator of public health impacts from combustion-related sources than PM mass. Quantifying the contribution of fossil fuel and biomass combustion to the EC and OC emissions and their temporal and spatial variations is critical for developing efficient legislative air pollution control measures and successful climate mitigation strategies. In this study, we used radiocarbon (14C) to separate and quantify fossil and biomass contributions to a time series of EC and OC collected at 3 locations in Salt Lake City (SLC). Aerosol samples were collected on quartz fiber filters and a modified OC/EC analyzer was used with the Swiss_4S protocol to isolate and trap the EC fraction. Together with the total carbon (TC) content of the samples, the EC was analyzed for its 14C content with accelerator mass spectrometry. The 14C of OC was derived as a mass balance difference between TC and EC. EC had an annual average fraction modern of 0.13±0.06 and did not vary significantly across seasons. OC had an annual average FM of 0.49±0.13, with the winter mean (0.43±0.11) lower than the summer mean (0.64±0.13) at the 5% significance level. While the 3 stations were chosen to represent a variety of environmental conditions within SLC, no major differences in this source partitioning were observed between stations. During winter, the major sources of air pollutants in SLC are motor vehicles and wood stove combustion and determining their relative contributions has been the subject of debate. Our results indicated that fossil fuels were the dominant source of carbonaceous aerosols during winter, contributing 87% or more of the total EC mass and 40-75% of the OC. This suggests that fossil fuel-derived emissions should be a target for improving air quality during winter in SLC.

Positron production using a 1.7 MV pelletron accelerator

NASA Astrophysics Data System (ADS)

Alcantara, K. F.; Crivelli, P.; Santos, A. C. F.

2013-04-01

We report the foremost phase of a fourth generation positron source, being constructed at the Federal University of Rio de Janeiro. Positron yields are reported by making use of the 19F(p,αe+e-)16O reaction, where the fluorine target is in the form of a CaF2 pellet. Positron production has been observed by detecting 511 keV annihilation gamma rays emerging from the irradiated CaF2 target.

Physics and applications of positron beams in an integrated PET/MR.

PubMed

Watson, Charles C; Eriksson, Lars; Kolb, Armin

2013-02-07

In PET/MR systems having the PET component within the uniform magnetic field interior to the MR, positron beams can be injected into the PET field of view (FOV) from unshielded emission sources external to it, as a consequence of the action of the Lorentz force on the transverse components of the positron's velocity. Such beams may be as small as a few millimeters in diameter, but extend 50 cm or more axially without appreciable divergence. Larger beams form 'phantoms' of annihilations in air that can be easily imaged, and that are essentially free of γ-ray attenuation and scatter effects, providing a unique tool for characterizing PET systems and reconstruction algorithms. Thin targets intersecting these beams can produce intense annihilation sources having the thickness of a sheet of paper, which are very useful for high resolution measurements, and difficult to achieve with conventional sources. Targeted beams can provide other point, line and surface sources for various applications, all without the need to have radioactivity within the FOV. In this paper we discuss the physical characteristics of positron beams in air and present examples of their applications.

Natural history of SLC11 genes in vertebrates: tales from the fish world.

PubMed

Neves, João V; Wilson, Jonathan M; Kuhl, Heiner; Reinhardt, Richard; Castro, L Filipe C; Rodrigues, Pedro N S

2011-04-18

The SLC11A1/Nramp1 and SLC11A2/Nramp2 genes belong to the SLC11/Nramp family of transmembrane divalent metal transporters, with SLC11A1 being associated with resistance to pathogens and SLC11A2 involved in intestinal iron uptake and transferrin-bound iron transport. Both members of the SLC11 gene family have been clearly identified in tetrapods; however SLC11A1 has never been documented in teleost fish and is believed to have been lost in this lineage during early vertebrate evolution. In the present work we characterized the SLC11 genes in teleosts and evaluated if the roles attributed to mammalian SLC11 genes are assured by other fish specific SLC11 gene members. Two different SLC11 genes were isolated in the European sea bass (Dicentrarchus. labrax), and named slc11a2-α and slc11a2-β, since both were found to be evolutionary closer to tetrapods SLC11A2, through phylogenetic analysis and comparative genomics. Induction of slc11a2-α and slc11a2-β in sea bass, upon iron modulation or exposure to Photobacterium damselae spp. piscicida, was evaluated in in vivo or in vitro experimental models. Overall, slc11a2-α was found to respond only to iron deficiency in the intestine, whereas slc11a2-β was found to respond to iron overload and bacterial infection in several tissues and also in the leukocytes. Our data suggests that despite the absence of slc11a1, its functions have been undertaken by one of the slc11a2 duplicated paralogs in teleost fish in a case of synfunctionalization, being involved in both iron metabolism and response to bacterial infection. This study provides, to our knowledge, the first example of this type of sub-functionalization in iron metabolism genes, illustrating how conserving the various functions of the SLC11 gene family is of crucial evolutionary importance.

Nondestructive examination using neutron activated positron annihilation

DOEpatents

Akers, Douglas W.; Denison, Arthur B.

2001-01-01

A method is provided for performing nondestructive examination of a metal specimen using neutron activated positron annihilation wherein the positron emitter source is formed within the metal specimen. The method permits in situ nondestructive examination and has the advantage of being capable of performing bulk analysis to determine embrittlement, fatigue and dislocation within a metal specimen.

Multifunctional ion transport properties of human SLC4A11: comparison of the SLC4A11-B and SLC4A11-C variants.

PubMed

Kao, Liyo; Azimov, Rustam; Shao, Xuesi M; Frausto, Ricardo F; Abuladze, Natalia; Newman, Debra; Aldave, Anthony J; Kurtz, Ira

2016-11-01

Congenital hereditary endothelial dystrophy (CHED), Harboyan syndrome (CHED with progressive sensorineural deafness), and potentially a subset of individuals with late-onset Fuchs' endothelial corneal dystrophy are caused by mutations in the SLC4A11 gene that results in corneal endothelial cell abnormalities. Originally classified as a borate transporter, the function of SLC4A11 as a transport protein remains poorly understood. Elucidating the transport function(s) of SLC4A11 is needed to better understand how its loss results in the aforementioned posterior corneal dystrophic disease processes. Quantitative PCR experiments demonstrated that, of the three known human NH 2 -terminal variants, SLC4A11-C is the major transcript expressed in human corneal endothelium. We studied the expression pattern of the three variants in mammalian HEK-293 cells and demonstrated that the SLC4A11-B and SLC4A11-C variants are plasma membrane proteins, whereas SLC4A11-A is localized intracellularly. SLC4A11-B and SLC4A11-C were shown to be multifunctional ion transporters capable of transporting H + equivalents in both a Na + -independent and Na + -coupled mode. In both transport modes, SLC4A11-C H + flux was significantly greater than SLC4A11-B. In the presence of ammonia, SLC4A11-B and SLC4A11-C generated inward currents that were comparable in magnitude. Chimera SLC4A11-C-NH 2 -terminus-SLC4A11-B experiments demonstrated that the SLC4A11-C NH 2 -terminus functions as an autoactivating domain, enhancing Na + -independent and Na + -coupled H + flux without significantly affecting the electrogenic NH 3 -H (n) + cotransport mode. All three modes of transport were significantly impaired in the presence of the CHED causing p.R109H (SLC4A11-C numbering) mutation. These complex ion transport properties need to be addressed in the context of corneal endothelial disease processes caused by mutations in SLC4A11. Copyright © 2016 the American Physiological Society.

Intense positron beam as a source for production of electron-positron plasma

NASA Astrophysics Data System (ADS)

Stoneking, M. R.; Horn-Stanja, J.; Stenson, E. V.; Pedersen, T. Sunn; Saitoh, H.; Hergenhahn, U.; Niemann, H.; Paschkowski, N.; Hugenschmidt, C.; Piochacz, C.

2016-10-01

We aim to produce magnetically confined, short Debye length electron-positron plasma and test predicted properties for such systems. A first challenge is obtaining large numbers of positrons; a table-top experiment (system size 5 cm) with a temperature less than 5 eV requires about 1010 positrons to have more than 10 Debye lengths in the system. The NEPOMUC facility at the FRM II research reactor in Germany is one of the world's most intense positron sources. We report on characterization (using a retarding field energy analyzer with magnetic field gradient) of the NEPOMUC beam as delivered to the open beam port at various beam energies and in both the re-moderated and primary beam configurations in order to design optimal trapping (and accumulation) schemes for production of electron-positron plasma. The intensity of the re-moderated (primary) beam is in the range 2 -3 x 107 /s (1 - 5 x 108 /s). The re-moderated beam is currently the most promising for direct injection and confinement experiments; it has a parallel energy spread of 15 - 35% and the transverse energy spread is 6 - 15% of the parallel energy. We report on the implications for injection and trapping in a dipole magnetic field as well as plans for beam development, in situ re-moderation, and accumulation. We also report results demonstrating a difference in phosphor luminescent response to low energy positrons versus electrons.

Computational methods for analyzing the transmission characteristics of a beta particle magnetic analysis system

NASA Technical Reports Server (NTRS)

Singh, J. J.

1979-01-01

Computational methods were developed to study the trajectories of beta particles (positrons) through a magnetic analysis system as a function of the spatial distribution of the radionuclides in the beta source, size and shape of the source collimator, and the strength of the analyzer magnetic field. On the basis of these methods, the particle flux, their energy spectrum, and source-to-target transit times have been calculated for Na-22 positrons as a function of the analyzer magnetic field and the size and location of the target. These data are in studies requiring parallel beams of positrons of uniform energy such as measurement of the moisture distribution in composite materials. Computer programs for obtaining various trajectories are included.

Solute carriers (SLCs) identified and characterized from kidney transcriptome of golden mahseer (Tor putitora) (Fam: Cyprinidae).

PubMed

Barat, Ashoktaru; Sahoo, Prabhati Kumari; Kumar, Rohit; Pande, Veena

2016-10-01

The solute carriers (SLC) are trans-membrane proteins, those regulate the transport of various substances (sugars, amino acids, nucleotides, inorganic cations/anions, metals, drugs etc.) across the cell membrane. There are more than 338 solute carriers (slc) reported in fishes that play crucial role in cellular influx and efflux. The study of solute carrier families may reveal many answers regarding the function of transporter genes in the species and their effect in the existing environment. Therefore, we performed RNA sequencing of kidney tissue of the golden mahseer (Tor putitora) using Illumina platform to identify the solute carrier families and characterized 24 putative functional genes under 15 solute carrier families. Out of 24 putative functional genes, 11 genes were differentially expressed in different tissues (head kidney, trunk kidney, spleen, liver, gill, muscle, intestine and brain) using qRT-PCR assay. The slc5a1, slc5a12, slc12a3, slc13a3, slc22a13 and slc26a6 were highly expressed in kidney. The slc15a2, slc25a47, slc33a1 and slc38a2 were highly expressed in brain and slc30a5 was over-expressed in gill. The unrooted phylogenetic trees of slc2, slc5, slc13 and slc33 were constructed using amino acid sequences of Homo sapiens, Salmo salar, Danio rerio, Cyprinus carpio and Tor putitora. It appears that all the putative solute carrier families are very much conserved in human and fish species including the present fish, golden mahseer. This study provides the first hand database of solute carrier families particularly transporter encoding proteins in the species. Copyright © 2016 Elsevier Inc. All rights reserved.

Positron Lifetime Modulation by Electric Field Induced Positronium Formation on a Gold Surface

DTIC Science & Technology

2012-03-22

Angular Momentum (3) ......................................................................... 11 Stopping Power (4...isotope from which it was born, diffused into the material before annihilation occurred. 6 The radioisotope used in this experiment is Na-22 which...that positrons may be useful in studying the internal structure of a wide variety of materials. The radioisotope positron source used in this

The development of cat testicular sperm cryopreservation protocols: Effects of tissue fragments or sperm cell suspension.

PubMed

Chatdarong, Kaywalee; Thuwanut, Paweena; Morrell, Jane M

2016-01-15

In endangered animals that have been found dead or sterilized for medical reasons, testis is the ultimate source of haploid DNA or sperm. Thus, preservation of testicular sperm may be performed to rescue their genetics. The aim of this study was to evaluate protocols for testicular sperm freezing: as tissue fragments or cell suspension in domestic cats as a model. A pair of testes from each cat (n = 9) were cut into eight equal pieces. Four randomly selected pieces were cryopreserved as: (1) tissue pieces using two-step freezing; (2) tissue pieces using a slow passive cooling device (CoolCell); (3) sperm suspension after single-layer centrifugation (SLC) through colloids; and (4) sperm suspension without being processed through SLC. A testicular piece from each cat served as fresh control. Testicular sperm membrane and DNA integrity were evaluated before, and after, the cryopreservation process. In addition, spermatogenic cell types (testicular sperm, spermatogonia, spermatocyte, and spermatid) present in the suspension samples were counted before and after SLC. The results found that testicular sperm membrane integrity in the suspension after SLC process was higher than that in the fragment form neither using the two-step nor CoolCell freezing, both before and after freezing (before freezing: 92.3 ± 3.4 vs. 81 ± 4.5 and 80.0 ± 7.0; after freezing: 84.5 ± 4.6 vs. 71.2 ± 12 and 76.2 ± 4.6; P ≤ 0.05). Testicular sperm DNA integrity was, however, not different among groups. Furthermore, the samples processed through the SLC had higher ration of sperm cells: other spermatogenic cells than those were not processed through the SLC (88.9 ± 3.8 vs. 30 ± 7.9; P ≤ 0.05). In summary, testicular sperm cryopreserved as a minced suspension is considered suitable in terms of preventing sperm membrane integrity, and SLC is considered a selection tool for enriching haploid sperm cells from castrated or postmortem cats. Copyright © 2016 Elsevier Inc. All rights reserved.

A proposed intense slow positron source based on 58Co

NASA Astrophysics Data System (ADS)

Brown, Benjamin L.; Denison, Art; Makowitz, Henry; Gidley, Dave; Frieze, Bill; Griffin, Henry; Encarnación, Pedro

1994-06-01

Positron beams have proven very useful for condensed matter and surface research. The highest intensity of the current operating positron beams is ˜109 slow e+/second. The goal of our proposal is to build an Intense Slow Positron Source (ISPS) demonstration beam (Phase I) of unprecedented brightness at the Idaho National Engineering Laboratory, INEL (up to 1010 slow e+/s at 5 keV over a <0.03 cm. diameter). This Phase I beam will prove the principles necessary to build a larger facility scale ISPS Phase II beam which will have a potential of 1013 e+/s, or ≳1012 e+/s over 0.03 cm. The INEL is an ideal location for the ISPS because of the fast breeder reactor EBR-II, which is perfectly suited to creating the positron emitting isotope 58Co, and the excellent radioactive materials handling capability and expertise. Sufficient expertise is available at INEL for the construction and operation of a user facility (Phase II).

Functional assessment of SLC4A11, an integral membrane protein mutated in corneal dystrophies

PubMed Central

Loganathan, Sampath K.; Schneider, Hans-Peter; Morgan, Patricio E.; Deitmer, Joachim W.

2016-01-01

SLC4A11, a member of the SLC4 family of bicarbonate transporters, is a widely expressed integral membrane protein, abundant in kidney and cornea. Mutations of SLC4A11 cause some cases of the blinding corneal dystrophies, congenital hereditary endothelial dystrophy, and Fuchs endothelial corneal dystrophy. These diseases are marked by fluid accumulation in the corneal stroma, secondary to defective fluid reabsorption by the corneal endothelium. The role of SLC4A11 in these corneal dystrophies is not firmly established, as SLC4A11 function remains unclear. To clarify the normal function(s) of SLC4A11, we characterized the protein following expression in the simple, low-background expression system Xenopus laevis oocytes. Since plant and fungal SLC4A11 orthologs transport borate, we measured cell swelling associated with accumulation of solute borate. The plant water/borate transporter NIP5;1 manifested borate transport, whereas human SLC4A11 did not. SLC4A11 supported osmotically driven water accumulation that was electroneutral and Na+ independent. Studies in oocytes and HEK293 cells could not detect Na+-coupled HCO3− transport or Cl−/HCO3− exchange by SLC4A11. SLC4A11 mediated electroneutral NH3 transport in oocytes. Voltage-dependent OH− or H+ movement was not measurable in SLC4A11-expressing oocytes, but SLC4A11-expressing HEK293 cells manifested low-level cytosolic acidification at baseline. In mammalian cells, but not oocytes, OH−/H+ conductance may arise when SLC4A11 activates another protein or itself is activated by another protein. These data argue against a role of human SLC4A11 in bicarbonate or borate transport. This work provides additional support for water and ammonia transport by SLC4A11. When expressed in oocytes, SLC4A11 transported NH3, not NH3/H+. PMID:27558157

Slc26a6: a cardiac chloride–hydroxyl exchanger and predominant chloride–bicarbonate exchanger of the mouse heart

PubMed Central

Alvarez, Bernardo V; Kieller, Dawn M; Quon, Anita L; Markovich, Daniel; Casey, Joseph R

2004-01-01

Bicarbonate facilitate more than 50% of pH recovery in the acidotic myocardium, and have roles in cardiac hypertrophy and steady-state pH regulation. To determine which bicarbonate transporters are responsible for this activity, we measured the expression levels of all known HCO3−–anion exchange proteins in mouse heart, by quantitative real time RT-PCR. Bicarbonate–anion exchangers are members of either the SLC4A or the SLC26A gene families. In neonatal and adult myocardium, AE1 (Slc4a1), AE2 (Slc4a2), AE3 (Slc4a3) (AE3fl and AE3c variants), Slc26a3 and Slc26a6 were expressed. Adult hearts expressed Slc26a3 and Slc4a1–3 mRNAs at similar levels, while Slc26a6 mRNA was about seven-fold higher than AE3, which was more abundant than any other. Immunohistochemistry revealed that Slc26a6 and AE3 are present in the plasma membrane of ventricular myocytes. Slc26a6 expression levels were higher in ventricle than atrium, whereas AE3 was detected only in ventricle. Cl−–HCO3− and Cl−–OH− exchange activity of SLC26A6 and AE3 were investigated in transfected HEK293 cells, using intracellular fluorescence measurements of 2′,7′-bis (2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF), to monitor intracellular pH (pHi). Rates of pHi change were measured under HCO3−-containing (Cl−–HCO3−) or nominally HCO3−-free (Cl−–OH−) conditions. HCO3− fluxes were similar for cells expressing AE3fl, SLC26A6 or Slc26a3, suggesting that they have similar transport activity. However, only SLC26A6 and Slc26a3 functioned as Cl−–OH− exchangers. Activation of α-adrenergic receptors, which stimulates protein kinase C, inhibited SLC26A6 Cl−–HCO3− exchange activity. We conclude that Slc26a6 is the predominant Cl−–HCO3− and Cl−–OH− exchanger of the myocardium and that Slc26a6 is negatively regulated upon α-adrenergic stimulation. PMID:15498800

Positron production using a 1.7 MV pelletron accelerator

DOE Office of Scientific and Technical Information (OSTI.GOV)

Alcantara, K. F.; Santos, A. C. F.; Crivelli, P.

2013-04-19

We report the foremost phase of a fourth generation positron source, being constructed at the Federal University of Rio de Janeiro. Positron yields are reported by making use of the {sup 19}F(p,{alpha}e{sup +}e{sup -}){sup 16}O reaction, where the fluorine target is in the form of a CaF{sub 2} pellet. Positron production has been observed by detecting 511 keV annihilation gamma rays emerging from the irradiated CaF{sub 2} target.

Studies of Positron Generation from Ultraintense Laser-Matter Interactions

NASA Astrophysics Data System (ADS)

Williams, Gerald Jackson

Laser-produced pair jets possess unique characteristics that offer great potential for their use in laboratory-astrophysics experiments to study energetic phenomenon such as relativistic shock accelerations. High-flux, high-energy positron sources may also be used to study relativistic pair plasmas and useful as novel diagnostic tools for high energy density conditions. Copious amounts of positrons are produced with MeV energies from directly irradiating targets with ultraintense lasers where relativistic electrons, accelerated by the laser field, drive positron-electron pair production. Alternatively, laser wakefield accelerated electrons can produce pairs by the same mechanisms inside a secondary converter target. This dissertation describes a series of novel experiments that investigate the characteristics and scaling of pair production from ultraintense lasers, which are designed to establish a robust platform for laboratory-based relativistic pair plasmas. Results include a simple power-law scaling to estimate the effective positron yield for elemental targets for any Maxwellian electron source, typical of direct laser-target interactions. To facilitate these measurements, a solenoid electromagnetic coil was constructed to focus emitted particles, increasing the effective collection angle of the detector and enabling the investigation of pair production from thin targets and low-Z materials. Laser wakefield electron sources were also explored as a compact, high repetition rate platform for the production of high energy pairs with potential applications to the creation of charge-neutral relativistic pair plasmas. Plasma accelerators can produce low-divergence electron beams with energies approaching a GeV at Hz frequencies. It was found that, even for high-energy positrons, energy loss and scattering mechanisms in the target create a fundamental limit to the divergence and energy spectrum of the emitted positrons. The potential future application of laser-generated pairs was considered by exploring the feasibility of radiographing an imploding inertial confinement fusion capsule at ignition- relevant conditions. For an in-flight areal density of 0.02-0.2 g/cm2, currently available positron sources can make density and spatial measurements of deuterium-tritium fuel cores where additional complications of full-scale experiments are expected to reduce the measurement sensitivity.

A Review of Recent Updates of Sea-Level Projections at Global and Regional Scales

NASA Technical Reports Server (NTRS)

Slangen, A. B. A.; Adloff, F.; Jevrejeva, S.; Leclercq, P. W.; Marzeion, B.; Wada, Yoshihide; Winkelmann, R.

2016-01-01

Sea-level change (SLC) is a much-studied topic in the area of climate research, integrating a range of climate science disciplines, and is expected to impact coastal communities around the world. As a result, this field is rapidly moving, and the knowledge and understanding of processes contributing to SLC is increasing. Here, we discuss noteworthy recent developments in the projection of SLC contributions and in the global mean and regional sea-level projections. For the Greenland Ice Sheet contribution to SLC, earlier estimates have been confirmed in recent research, but part of the source of this contribution has shifted from dynamics to surface melting. New insights into dynamic discharge processes and the onset of marine ice sheet instability increase the projected range for the Antarctic contribution by the end of the century. The contribution from both ice sheets is projected to increase further in the coming centuries to millennia. Recent updates of the global glacier outline database and new global glacier models have led to slightly lower projections for the glacier contribution to SLC (7-17 cm by 2100), but still project the glaciers to be an important contribution. For global mean sea-level projections, the focus has shifted to better estimating the uncertainty distributions of the projection time series, which may not necessarily follow a normal distribution. Instead, recent studies use skewed distributions with longer tails to higher uncertainties. Regional projections have been used to study regional uncertainty distributions, and regional projections are increasingly being applied to specific regions, countries, and coastal areas.

Effect of Dopamine Transporter Gene (SLC6A3) Variation on Dorsal Anterior Cingulate Function in Attention-Deficit/Hyperactivity Disorder

PubMed Central

Brown, Ariel B.; Biederman, Joseph; Valera, Eve M.; Doyle, Alysa E.; Bush, George; Spencer, Thomas; Monuteaux, Michael C.; Mick, Eric; Whitfield-Gabrieli, Susan; Makris, Nikos; LaViolette, Peter S.; Oscar-Berman, Marlene; Faraone, Stephen V.; Seidman, Larry J.

2010-01-01

Objective - Although Attention-Deficit/Hyperactivity Disorder (ADHD) is associated both with brain alterations in attention and executive function (EF) circuitry and with genetic variations within the dopamine system (including the dopamine transporter gene [SLC6A3]), few studies have directly investigated how genetic variations are linked to brain alterations. We sought to examine how a polymorphism in the 3’ untranslated region (UTR) of SLC6A3, associated with ADHD in meta-analysis, might contribute to variation in dorsal anterior cingulate cortex (dACC) function in subjects with ADHD. Method - We collected fMRI scans of 42 individuals with ADHD, all of European descent and over the age of 17, while they performed the Multi-Source Interference Task (MSIT), a cognitive task shown to activate dACC. SLC6A3 3’ UTR variable number tandem repeat (VNTR) polymorphisms were genotyped and brain activity was compared for groups based on allele status. Results - ADHD individuals homozygous for the 10R allele showed significant hypoactivation in the left dACC compared to 9R-carriers. Exploratory analysis also showed trends toward hypoactivation in the 10R homozygotes in left cerebellar vermis and right lateral prefrontal cortex. Further breakdown of genotype groups showed similar activation in individuals heterozygous and homozygous for the 9R allele. Conclusions - Alterations in activation of attention and EF networks found previously to be involved in ADHD are likely influenced by SLC6A3 genotype. This genotype may contribute to heterogeneity of brain alterations found within ADHD samples. PMID:19676101

Novel riboflavin transporter family RFVT/SLC52: identification, nomenclature, functional characterization and genetic diseases of RFVT/SLC52.

PubMed

Yonezawa, Atsushi; Inui, Ken-ichi

2013-01-01

Riboflavin, a water-soluble vitamin also known as vitamin B2, is essential for normal cellular functions. Riboflavin transporters play important roles in its homeostasis. Recently, three novel riboflavin transporters were identified, and designated as RFT1, RFT2 and RFT3. Because the RFTs did not show similarity to other SLC transporters, and RFT1 and RFT3 are similar in sequence and function, they were assigned into a new SLC family, SLC52. Subsequently, RFT1/GPR172B, RFT3/GPR172A and RFT2/C20orf54 were renamed as RFVT1/SLC52A1, RFVT2/SLC52A2 and RFVT3/SLC52A3, respectively. In this review, we summarize recent findings on the cloning, nomenclature, functional characterization and genetic diseases of RFVT1/SLC52A1, RFVT2/SLC52A2 and RFVT3/SLC52A3. Copyright © 2012 Elsevier Ltd. All rights reserved.

Association between SLC11A1 (NRAMP1) polymorphisms and susceptibility to tuberculosis in Chinese Holstein cattle.

PubMed

Liu, Kaihua; Zhang, Bin; Teng, Zhaochun; Wang, Youtao; Dong, Guodong; Xu, Cong; Qin, Bo; Song, Chunlian; Chai, Jun; Li, Yang; Shi, Xianwei; Shu, Xianghua; Zhang, Yifang

2017-03-01

We investigated the associations between SLC11A1 polymorphisms and susceptibility to tuberculosis (TB) in Chinese Holstein cattle, using a case-control study of 136 animals that had positive reactions to TB tests and showed symptoms and 96 animals that had negative reactions to tests and showed no symptoms. Polymerase chain reaction (PCR) sequencing and the restriction fragment length polymorphism (RFLP) technique were used to detect and determine SLC11A1 polymorphisms. Association analysis identified significant correlations between SLC11A1 polymorphisms and susceptibility/resistance to TB, and two genetic markers for SLC11A1 were established using PCR-RFLP. Sequence alignment of SLC11A1 revealed seven single-nucleotide polymorphisms (SNPs). This is the first report of MaeII PCR-RFLP markers for the SLC11A1-SNP3 site and PstI PCR-RFLP markers for the SLC11A1-SNP5 and SLC11A1-SNP6 sites in Chinese Holstein cattle. Logistic regression analysis indicated that SLC11A1-SNP1, SLC11A1-SNP3, and SLC11A1-SNP5 were significantly associated with susceptibility/resistance to TB. Two genotypes of SLC11A1-SNP3 were susceptible to TB, whereas one genotype of SLC11A1-SNP1 and two genotypes of SLC11A1-SNP5 were resistant. Haplotype analysis showed that nine haplotypes were potentially resistant to TB. After Bonferroni correction, three of the haplotypes remained significantly associated with TB resistance. SLC11A1 is a useful candidate gene related to TB in Chinese Holstein cattle. Copyright © 2016 Elsevier Ltd. All rights reserved.

Answer to Question {number_sign}30 [{open_quote}{open_quote}How are positrons moderated?,{close_quote}{close_quote} Thomas D. Rossing, Am. J. Phys. {bold 63}(12), 1065 (1995)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weber, M.; Lynn, K.G.

1996-07-01

The positrons from {beta}{sup +} decaying sources loss energyat a much faster rate than they annihilate. As the energy of the positrons drops, core excitations, plasmon excitation, electron/hole pair creation, and phonon scattering are the dominant processes of further energy loss.

Extended gamma-ray sources around pulsars constrain the origin of the positron flux at Earth.

PubMed

Abeysekara, A U; Albert, A; Alfaro, R; Alvarez, C; Álvarez, J D; Arceo, R; Arteaga-Velázquez, J C; Avila Rojas, D; Ayala Solares, H A; Barber, A S; Bautista-Elivar, N; Becerril, A; Belmont-Moreno, E; BenZvi, S Y; Berley, D; Bernal, A; Braun, J; Brisbois, C; Caballero-Mora, K S; Capistrán, T; Carramiñana, A; Casanova, S; Castillo, M; Cotti, U; Cotzomi, J; Coutiño de León, S; De León, C; De la Fuente, E; Dingus, B L; DuVernois, M A; Díaz-Vélez, J C; Ellsworth, R W; Engel, K; Enríquez-Rivera, O; Fiorino, D W; Fraija, N; García-González, J A; Garfias, F; Gerhardt, M; González Muñoz, A; González, M M; Goodman, J A; Hampel-Arias, Z; Harding, J P; Hernández, S; Hernández-Almada, A; Hinton, J; Hona, B; Hui, C M; Hüntemeyer, P; Iriarte, A; Jardin-Blicq, A; Joshi, V; Kaufmann, S; Kieda, D; Lara, A; Lauer, R J; Lee, W H; Lennarz, D; Vargas, H León; Linnemann, J T; Longinotti, A L; Luis Raya, G; Luna-García, R; López-Coto, R; Malone, K; Marinelli, S S; Martinez, O; Martinez-Castellanos, I; Martínez-Castro, J; Martínez-Huerta, H; Matthews, J A; Miranda-Romagnoli, P; Moreno, E; Mostafá, M; Nellen, L; Newbold, M; Nisa, M U; Noriega-Papaqui, R; Pelayo, R; Pretz, J; Pérez-Pérez, E G; Ren, Z; Rho, C D; Rivière, C; Rosa-González, D; Rosenberg, M; Ruiz-Velasco, E; Salazar, H; Salesa Greus, F; Sandoval, A; Schneider, M; Schoorlemmer, H; Sinnis, G; Smith, A J; Springer, R W; Surajbali, P; Taboada, I; Tibolla, O; Tollefson, K; Torres, I; Ukwatta, T N; Vianello, G; Weisgarber, T; Westerhoff, S; Wisher, I G; Wood, J; Yapici, T; Yodh, G; Younk, P W; Zepeda, A; Zhou, H; Guo, F; Hahn, J; Li, H; Zhang, H

2017-11-17

The unexpectedly high flux of cosmic-ray positrons detected at Earth may originate from nearby astrophysical sources, dark matter, or unknown processes of cosmic-ray secondary production. We report the detection, using the High-Altitude Water Cherenkov Observatory (HAWC), of extended tera-electron volt gamma-ray emission coincident with the locations of two nearby middle-aged pulsars (Geminga and PSR B0656+14). The HAWC observations demonstrate that these pulsars are indeed local sources of accelerated leptons, but the measured tera-electron volt emission profile constrains the diffusion of particles away from these sources to be much slower than previously assumed. We demonstrate that the leptons emitted by these objects are therefore unlikely to be the origin of the excess positrons, which may have a more exotic origin. Copyright © 2017, American Association for the Advancement of Science.

Transport by SLC5A8 with subsequent inhibition of histone deacetylase 1 (HDAC1) and HDAC3 underlies the antitumor activity of 3-bromopyruvate.

PubMed

Thangaraju, Muthusamy; Karunakaran, Senthil K; Itagaki, Shiro; Gopal, Elangovan; Elangovan, Selvakumar; Prasad, Puttur D; Ganapathy, Vadivel

2009-10-15

3-bromopyruvate is an alkylating agent with antitumor activity. It is currently believed that blockade of adenosine triphosphate production from glycolysis and mitochondria is the primary mechanism responsible for this antitumor effect. The current studies uncovered a new and novel mechanism for the antitumor activity of 3-bromopyruvate. The transport of 3-bromopyruvate by sodium-coupled monocarboxylate transporter SMCT1 (SLC5A8), a tumor suppressor and a sodium (Na+)-coupled, electrogenic transporter for short-chain monocarboxylates, was studied using a mammalian cell expression and the Xenopus laevis oocyte expression systems. The effect of 3-bromopyruvate on histone deacetylases (HDACs) was monitored using the lysate of the human breast cancer cell line MCF7 and human recombinant HDAC isoforms as the enzyme sources. Cell viability was monitored by fluorescence-activated cell-sorting analysis and colony-formation assay. The acetylation status of histone H4 was evaluated by Western blot analysis. 3-Bromopyruvate is a transportable substrate for SLC5A8, and that transport process is Na+-coupled and electrogenic. MCF7 cells did not express SLC5A8 and were not affected by 3-bromopyruvate. However, when transfected with SLC5A8 or treated with inhibitors of DNA methylation, these cells underwent apoptosis in the presence of 3-bromopyruvate. This cell death was associated with the inhibition of HDAC1/HDAC3. Studies with different isoforms of human recombinant HDACs identified HDAC1 and HDAC3 as the targets for 3-bromopyruvate. 3-Bromopyruvate was transported into cells actively through the tumor suppressor SLC5A8, and the process was energized by an electrochemical Na+ gradient. Ectopic expression of the transporter in MCF7 cells led to apoptosis, and the mechanism involved the inhibition of HDAC1/HDAC3. Copyright (c) 2009 American Cancer Society.

Diversity in the glucose transporter-4 gene (SLC2A4) in humans reflects the action of natural selection along the old-world primates evolution.

PubMed

Tarazona-Santos, Eduardo; Fabbri, Cristina; Yeager, Meredith; Magalhaes, Wagner C; Burdett, Laurie; Crenshaw, Andrew; Pettener, Davide; Chanock, Stephen J

2010-03-23

Glucose is an important source of energy for living organisms. In vertebrates it is ingested with the diet and transported into the cells by conserved mechanisms and molecules, such as the trans-membrane Glucose Transporters (GLUTs). Members of this family have tissue specific expression, biochemical properties and physiologic functions that together regulate glucose levels and distribution. GLUT4 -coded by SLC2A4 (17p13) is an insulin-sensitive transporter with a critical role in glucose homeostasis and diabetes pathogenesis, preferentially expressed in the adipose tissue, heart muscle and skeletal muscle. We tested the hypothesis that natural selection acted on SLC2A4. We re-sequenced SLC2A4 and genotyped 104 SNPs along a approximately 1 Mb region flanking this gene in 102 ethnically diverse individuals. Across the studied populations (African, European, Asian and Latin-American), all the eight common SNPs are concentrated in the N-terminal region upstream of exon 7 ( approximately 3700 bp), while the C-terminal region downstream of intron 6 ( approximately 2600 bp) harbors only 6 singletons, a pattern that is not compatible with neutrality for this part of the gene. Tests of neutrality based on comparative genomics suggest that: (1) episodes of natural selection (likely a selective sweep) predating the coalescent of human lineages, within the last 25 million years, account for the observed reduced diversity downstream of intron 6 and, (2) the target of natural selection may not be in the SLC2A4 coding sequence. We propose that the contrast in the pattern of genetic variation between the N-terminal and C-terminal regions are signatures of the action of natural selection and thus follow-up studies should investigate the functional importance of different regions of the SLC2A4 gene.

Conditionally Immortal Slc4a11-/- Mouse Corneal Endothelial Cell Line Recapitulates Disrupted Glutaminolysis Seen in Slc4a11-/- Mouse Model.

PubMed

Zhang, Wenlin; Ogando, Diego G; Kim, Edward T; Choi, Moon-Jung; Li, Hongde; Tenessen, Jason M; Bonanno, Joseph A

2017-07-01

To establish conditionally immortal mouse corneal endothelial cell lines with genetically matched Slc4a11+/+ and Slc4a11-/- mice as a model for investigating pathology and therapies for SLC4A11 associated congenital hereditary endothelial dystrophy (CHED) and Fuchs' endothelial corneal dystrophy. We intercrossed H-2Kb-tsA58 mice (Immortomouse) expressing an IFN-γ dependent and temperature-sensitive mutant of the SV40 large T antigen (tsTAg) with Slc4a11+/+ and Slc4a11-/- C57BL/6 mice. The growth characteristics of the cell lines was assessed by doubling time. Ion transport activities (Na+/H+ exchange, bicarbonate, lactate, and Slc4a11 ammonia transport) were analyzed by intracellular pH measurement. The metabolic status of the cell lines was assessed by analyzing TCA cycle intermediates via gas chromatography mass spectrometry (GC-MS). The immortalized Slc4a11+/+ and Slc4a11-/- mouse corneal endothelial cells (MCECs) remained proliferative through passage 49 and maintained similar active ion transport activity. As expected, proliferation was temperature sensitive and IFN-γ dependent. Slc4a11-/- MCECs exhibited decreased proliferative capacity, reduced NH3:H+ transport, altered expression of glutaminolysis enzymes similar to the Slc4a11-/- mouse, and reduced proportion of TCA cycle intermediates derived from glutamine with compensatory increases in glucose flux compared with Slc4a11+/+ MCECs. This is the first report of the immortalization of MCECs. Ion transport of the immortalized endothelial cells remains active, except for NH3:H+ transporter activity in Slc4a11-/- MCECs. Furthermore, Slc4a11-/- MCECs recapitulate the glutaminolysis defects observed in Slc4a11-/- mouse corneal endothelium, providing an excellent tool to study the pathogenesis of SLC4A11 mutations associated with corneal endothelial dystrophies and to screen potential therapeutic agents.

Decaying fermionic dark matter search with CALET

NASA Astrophysics Data System (ADS)

Bhattacharyya, S.; Motz, H.; Torii, S.; Asaoka, Y.

2017-08-01

The ISS-based CALET (CALorimetric Electron Telescope) detector can play an important role in indirect search for Dark Matter (DM), measuring the electron+positron flux in the TeV region for the first time directly. With its fine energy resolution of approximately 2% and good proton rejection ratio (1:105) it has the potential to search for fine structures in the Cosmic Ray (CR) electron spectrum. In this context we discuss the ability of CALET to discern between signals originating from astrophysical sources and DM decay. We fit a parametrization of the local interstellar electron and positron spectra to current measurements, with either a pulsar or 3-body decay of fermionic DM as the extra source causing the positron excess. The expected CALET data for scenarios in which DM decay explains the excess are calculated and analyzed. The signal from this particular 3-body DM decay which can explain the recent measurements from the AMS-02 experiment is shown to be distinguishable from a single pulsar source causing the positron excess by 5 years of observation with CALET, based on the shape of the spectrum. We also study the constraints from diffuse γ-ray data on this DM-only explanation of the positron excess and show that especially for the possibly remaining parameter space a clearly identifiable signature in the CR electron spectrum exists.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bhattacharyya, S.; Torii, S.; Motz, H.

The ISS-based CALET (CALorimetric Electron Telescope) detector can play an important role in indirect search for Dark Matter (DM), measuring the electron+positron flux in the TeV region for the first time directly. With its fine energy resolution of approximately 2% and good proton rejection ratio (1:10{sup 5}) it has the potential to search for fine structures in the Cosmic Ray (CR) electron spectrum. In this context we discuss the ability of CALET to discern between signals originating from astrophysical sources and DM decay. We fit a parametrization of the local interstellar electron and positron spectra to current measurements, with eithermore » a pulsar or 3-body decay of fermionic DM as the extra source causing the positron excess. The expected CALET data for scenarios in which DM decay explains the excess are calculated and analyzed. The signal from this particular 3-body DM decay which can explain the recent measurements from the AMS−02 experiment is shown to be distinguishable from a single pulsar source causing the positron excess by 5 years of observation with CALET, based on the shape of the spectrum. We also study the constraints from diffuse γ-ray data on this DM-only explanation of the positron excess and show that especially for the possibly remaining parameter space a clearly identifiable signature in the CR electron spectrum exists.« less

Differential expression of the Slc4 bicarbonate transporter family in murine corneal endothelium and cell culture.

PubMed

Shei, William; Liu, Jun; Htoon, Hla M; Aung, Tin; Vithana, Eranga N

2013-01-01

To characterize the relative expression levels of all the solute carrier 4 (Slc4) transporter family members (Slc4a1-Slc4a11) in murine corneal endothelium using real-time quantitative (qPCR), to identify further important members besides Slc4a11 and Slc4a4, and to explore how close to the baseline levels the gene expressions remain after cells have been subjected to expansion and culture. Descemet's membrane-endothelial layers of 8-10-week-old C57BL6 mice were stripped from corneas and used for both primary cell culture and direct RNA extraction. Total RNA (from uncultured cells as well as cultured cells at passages 2 and 7) was reverse transcribed, and the cDNA was used for real time qPCR using specific primers for all the Slc4 family members. The geNorm method was applied to determine the most stable housekeeping genes and normalization factor, which was calculated from multiple housekeeping genes for more accurate and robust quantification. qPCR analyses revealed that all Slc4 bicarbonate transporter family members were expressed in mouse corneal endothelium. Slc4a11 showed the highest expression, which was approximately three times higher than that of Slc4a4 (3.4±0.3; p=0.004). All Slc4 genes were also expressed in cultured cells, and interestingly, the expression of Slc4a11 in cultured cells was significantly reduced by approximately 20-fold (0.05±0.001; p=0.000001) in early passage and by approximately sevenfold (0.14±0.002; p=0.000002) in late passage cells. Given the known involvement of SLC4A4 and SLC4A11 in corneal dystrophies, we speculate that the other two highly expressed genes in the uncultured corneal endothelium, SLC4A2 and SLC4A7, are worthy of being considered as potential candidate genes for corneal endothelial diseases. Moreover, as cell culture can affect expression levels of Slc4 genes, caution and careful design of experiments are necessary when undertaking studies of Slc4-mediated ion transport in cultured cells.

Physical models and primary design of reactor based slow positron source at CMRR

NASA Astrophysics Data System (ADS)

Wang, Guanbo; Li, Rundong; Qian, Dazhi; Yang, Xin

2018-07-01

Slow positron facilities are widely used in material science. A high intensity slow positron source is now at the design stage based on the China Mianyang Research Reactor (CMRR). This paper describes the physical models and our primary design. We use different computer programs or mathematical formula to simulate different physical process, and validate them by proper experiments. Considering the feasibility, we propose a primary design, containing a cadmium shield, a honeycomb arranged W tubes assembly, electrical lenses, and a solenoid. It is planned to be vertically inserted in the Si-doping channel. And the beam intensity is expected to be 5 ×109

Combined Deletion of Slc30a7 and Slc30a8 Unmasks a Critical Role for ZnT8 in Glucose-Stimulated Insulin Secretion

PubMed Central

Syring, Kristen E.; Boortz, Kayla A.; Oeser, James K.; Ustione, Alessandro; Platt, Kenneth A.; Shadoan, Melanie K.; McGuinness, Owen P.; Piston, David W.; Powell, David R.

2016-01-01

Polymorphisms in the SLC30A8 gene, which encodes the ZnT8 zinc transporter, are associated with altered susceptibility to type 2 diabetes (T2D), and SLC30A8 haploinsufficiency is protective against the development of T2D in obese humans. SLC30A8 is predominantly expressed in pancreatic islet β-cells, but surprisingly, multiple knockout mouse studies have shown little effect of Slc30a8 deletion on glucose tolerance or glucose-stimulated insulin secretion (GSIS). Multiple other Slc30a isoforms are expressed at low levels in pancreatic islets. We hypothesized that functional compensation by the Slc30a7 isoform, which encodes ZnT7, limits the impact of Slc30a8 deletion on islet function. We therefore analyzed the effect of Slc30a7 deletion alone or in combination with Slc30a8 on in vivo glucose metabolism and GSIS in isolated islets. Deletion of Slc30a7 alone had complex effects in vivo, impairing glucose tolerance and reducing the glucose-stimulated increase in plasma insulin levels, hepatic glycogen levels, and pancreatic insulin content. Slc30a7 deletion also affected islet morphology and increased the ratio of islet α- to β-cells. However, deletion of Slc30a7 alone had no effect on GSIS in isolated islets, whereas combined deletion of Slc30a7 and Slc30a8 abolished GSIS. These data demonstrate that the function of ZnT8 in islets can be unmasked by removal of ZnT7 and imply that ZnT8 may affect T2D susceptibility through actions in other tissues where it is expressed at low levels rather than through effects on pancreatic islet function. PMID:27754787

Action Potential Shortening and Impairment of Cardiac Function by Ablation of Slc26a6.

PubMed

Sirish, Padmini; Ledford, Hannah A; Timofeyev, Valeriy; Thai, Phung N; Ren, Lu; Kim, Hyo Jeong; Park, Seojin; Lee, Jeong Han; Dai, Gu; Moshref, Maryam; Sihn, Choong-Ryoul; Chen, Wei Chun; Timofeyeva, Maria Valeryevna; Jian, Zhong; Shimkunas, Rafael; Izu, Leighton T; Chiamvimonvat, Nipavan; Chen-Izu, Ye; Yamoah, Ebenezer N; Zhang, Xiao-Dong

2017-10-01

Intracellular pH (pH i ) is critical to cardiac excitation and contraction; uncompensated changes in pH i impair cardiac function and trigger arrhythmia. Several ion transporters participate in cardiac pH i regulation. Our previous studies identified several isoforms of a solute carrier Slc26a6 to be highly expressed in cardiomyocytes. We show that Slc26a6 mediates electrogenic Cl - /HCO 3 - exchange activities in cardiomyocytes, suggesting the potential role of Slc26a6 in regulation of not only pH i , but also cardiac excitability. To test the mechanistic role of Slc26a6 in the heart, we took advantage of Slc26a6 knockout ( Slc26a6 -/ - ) mice using both in vivo and in vitro analyses. Consistent with our prediction of its electrogenic activities, ablation of Slc26a6 results in action potential shortening. There are reduced Ca 2+ transient and sarcoplasmic reticulum Ca 2+ load, together with decreased sarcomere shortening in Slc26a6 -/ - cardiomyocytes. These abnormalities translate into reduced fractional shortening and cardiac contractility at the in vivo level. Additionally, pH i is elevated in Slc26a6 -/ - cardiomyocytes with slower recovery kinetics from intracellular alkalization, consistent with the Cl - /HCO 3 - exchange activities of Slc26a6. Moreover, Slc26a6 -/ - mice show evidence of sinus bradycardia and fragmented QRS complex, supporting the critical role of Slc26a6 in cardiac conduction system. Our study provides mechanistic insights into Slc26a6, a unique cardiac electrogenic Cl - /HCO 3 - transporter in ventricular myocytes, linking the critical roles of Slc26a6 in regulation of pH i , excitability, and contractility. pH i is a critical regulator of other membrane and contractile proteins. Future studies are needed to investigate possible changes in these proteins in Slc26a6 -/ - mice. © 2017 American Heart Association, Inc.

The CFTR trafficking mutation F508del inhibits the constitutive activity of SLC26A9.

PubMed

Bertrand, Carol A; Mitra, Shalini; Mishra, Sanjay K; Wang, Xiaohui; Zhao, Yu; Pilewski, Joseph M; Madden, Dean R; Frizzell, Raymond A

2017-06-01

Several members of the SLC26A family of anion transporters associate with CFTR, forming complexes in which CFTR and SLC26A functions are reciprocally regulated. These associations are thought to be facilitated by PDZ scaffolding interactions. CFTR has been shown to be positively regulated by NHERF-1, and negatively regulated by CAL in airway epithelia. However, it is unclear which PDZ-domain protein(s) interact with SLC26A9, a SLC26A family member found in airway epithelia. We have previously shown that primary, human bronchial epithelia (HBE) from non-CF donors exhibit constitutive anion secretion attributable to SLC26A9. However, constitutive anion secretion is absent in HBE from CF donors. We examined whether changes in SLC26A9 constitutive activity could be attributed to a loss of CFTR trafficking, and what role PDZ interactions played. HEK293 coexpressing SLC26A9 with the trafficking mutant F508del CFTR exhibited a significant reduction in constitutive current compared with cells coexpressing SLC26A9 and wt CFTR. We found that SLC26A9 exhibits complex glycosylation when coexpressed with F508del CFTR, but its expression at the plasma membrane is decreased. SLC26A9 interacted with both NHERF-1 and CAL, and its interaction with both significantly increased with coexpression of wt CFTR. However, coexpression with F508del CFTR only increased SLC26A9's interaction with CAL. Mutation of SLC26A9's PDZ motif decreased this association with CAL, and restored its constitutive activity. Correcting aberrant F508del CFTR trafficking in CF HBE with corrector VX-809 also restored SLC26A9 activity. We conclude that when SLC26A9 is coexpressed with F508del CFTR, its trafficking defect leads to a PDZ motif-sensitive intracellular retention of SLC26A9. Copyright © 2017 the American Physiological Society.

Reduced Slc6a15 in Nucleus Accumbens D2-Neurons Underlies Stress Susceptibility.

PubMed

Chandra, Ramesh; Francis, T Chase; Nam, Hyungwoo; Riggs, Lace M; Engeln, Michel; Rudzinskas, Sarah; Konkalmatt, Prasad; Russo, Scott J; Turecki, Gustavo; Iniguez, Sergio D; Lobo, Mary Kay

2017-07-05

Previous research demonstrates that Slc6a15, a neutral amino acid transporter, is associated with depression susceptibility. However, no study examined Slc6a15 in the ventral striatum [nucleus accumbens (NAc)] in depression. Given our previous characterization of Slc6a15 as a striatal dopamine receptor 2 (D2)-neuron-enriched gene, we examined the role of Slc6a15 in NAc D2-neurons in mediating susceptibility to stress in male mice. First, we showed that Slc6a15 mRNA was reduced in NAc of mice susceptible to chronic social defeat stress (CSDS), a paradigm that produces behavioral and molecular adaptations that resemble clinical depression. Consistent with our preclinical data, we observed Slc6a15 mRNA reduction in NAc of individuals with major depressive disorder (MDD). The Slc6a15 reduction in NAc occurred selectively in D2-neurons. Next, we used Cre-inducible viruses combined with D2-Cre mice to reduce or overexpress Slc6a15 in NAc D2-neurons. Slc6a15 reduction in D2-neurons caused enhanced susceptibility to a subthreshold social defeat stress (SSDS) as observed by reduced social interaction, while a reduction in social interaction following CSDS was not observed when Slc6a15 expression in D2-neurons was restored. Finally, since both D2-medium spiny neurons (MSNs) and D2-expressing choline acetyltransferase (ChAT) interneurons express Slc6a15, we examined Slc6a15 protein in these interneurons after CSDS. Slc6a15 protein was unaltered in ChAT interneurons. Consistent with this, reducing Slc5a15 selectively in NAc D2-MSNs, using A2A-Cre mice that express Cre selectively in D2-MSNs, caused enhanced susceptibility to SSDS. Collectively, our data demonstrate that reduced Slc6a15 in NAc occurs in MDD individuals and that Slc6a15 reduction in NAc D2-neurons underlies stress susceptibility. SIGNIFICANCE STATEMENT Our study demonstrates a role for reduced Slc6a15, a neutral amino acid transporter, in nucleus accumbens (NAc) in depression and stress susceptibility. The reduction of Slc6a15 occurs selectively in the NAc D2-neurons. Genetic reduction of Slc6a15 induces susceptibility to a subthreshold stress, while genetic overexpression in D2-neurons prevents social avoidance after chronic social defeat stress. Copyright © 2017 the authors 0270-6474/17/376527-12$15.00/0.

Reduced Slc6a15 in Nucleus Accumbens D2-Neurons Underlies Stress Susceptibility

PubMed Central

Nam, Hyungwoo; Engeln, Michel; Konkalmatt, Prasad; Iniguez, Sergio D.

2017-01-01

Previous research demonstrates that Slc6a15, a neutral amino acid transporter, is associated with depression susceptibility. However, no study examined Slc6a15 in the ventral striatum [nucleus accumbens (NAc)] in depression. Given our previous characterization of Slc6a15 as a striatal dopamine receptor 2 (D2)-neuron-enriched gene, we examined the role of Slc6a15 in NAc D2-neurons in mediating susceptibility to stress in male mice. First, we showed that Slc6a15 mRNA was reduced in NAc of mice susceptible to chronic social defeat stress (CSDS), a paradigm that produces behavioral and molecular adaptations that resemble clinical depression. Consistent with our preclinical data, we observed Slc6a15 mRNA reduction in NAc of individuals with major depressive disorder (MDD). The Slc6a15 reduction in NAc occurred selectively in D2-neurons. Next, we used Cre-inducible viruses combined with D2-Cre mice to reduce or overexpress Slc6a15 in NAc D2-neurons. Slc6a15 reduction in D2-neurons caused enhanced susceptibility to a subthreshold social defeat stress (SSDS) as observed by reduced social interaction, while a reduction in social interaction following CSDS was not observed when Slc6a15 expression in D2-neurons was restored. Finally, since both D2-medium spiny neurons (MSNs) and D2-expressing choline acetyltransferase (ChAT) interneurons express Slc6a15, we examined Slc6a15 protein in these interneurons after CSDS. Slc6a15 protein was unaltered in ChAT interneurons. Consistent with this, reducing Slc5a15 selectively in NAc D2-MSNs, using A2A-Cre mice that express Cre selectively in D2-MSNs, caused enhanced susceptibility to SSDS. Collectively, our data demonstrate that reduced Slc6a15 in NAc occurs in MDD individuals and that Slc6a15 reduction in NAc D2-neurons underlies stress susceptibility. SIGNIFICANCE STATEMENT Our study demonstrates a role for reduced Slc6a15, a neutral amino acid transporter, in nucleus accumbens (NAc) in depression and stress susceptibility. The reduction of Slc6a15 occurs selectively in the NAc D2-neurons. Genetic reduction of Slc6a15 induces susceptibility to a subthreshold stress, while genetic overexpression in D2-neurons prevents social avoidance after chronic social defeat stress. PMID:28576941

Investigation of the fatty acid transporter-encoding genes SLC27A3 and SLC27A4 in autism.

PubMed

Maekawa, Motoko; Iwayama, Yoshimi; Ohnishi, Tetsuo; Toyoshima, Manabu; Shimamoto, Chie; Hisano, Yasuko; Toyota, Tomoko; Balan, Shabeesh; Matsuzaki, Hideo; Iwata, Yasuhide; Takagai, Shu; Yamada, Kohei; Ota, Motonori; Fukuchi, Satoshi; Okada, Yohei; Akamatsu, Wado; Tsujii, Masatsugu; Kojima, Nobuhiko; Owada, Yuji; Okano, Hideyuki; Mori, Norio; Yoshikawa, Takeo

2015-11-09

The solute carrier 27A (SLC27A) gene family encodes fatty acid transport proteins (FATPs) and includes 6 members. During fetal and postnatal periods of development, the growing brain requires a reliable supply of fatty acids. Because autism spectrum disorders (ASD) are now recognized as disorders caused by impaired early brain development, it is possible that functional abnormalities of SLC27A genes may contribute to the pathogenesis of ASD. Here, we confirmed the expression of SLC27A3 and SLC27A4 in human neural stem cells derived from human induced pluripotent stem cells, which suggested their involvement in the developmental stage of the central nervous system. Additionally, we resequenced the SLC27A3 and SLC27A4 genes using 267 ASD patient and 1140 control samples and detected 47 (44 novel and 29 nonsynonymous) and 30 (17 novel and 14 nonsynonymous) variants for the SLC27A3 and SLC27A4, respectively, revealing that they are highly polymorphic with multiple rare variants. The SLC27A4 Ser209 allele was more frequently represented in ASD samples. Furthermore, we showed that a SLC27A4 Ser209 mutant resulted in significantly higher fluorescently-labeled fatty acid uptake into bEnd3 cells, a mouse brain capillary-derived endothelial cell line, compared with SLC27A4 Gly209, suggesting that the functional change may contribute to ASD pathophysiology.

Investigation of the fatty acid transporter-encoding genes SLC27A3 and SLC27A4 in autism

PubMed Central

Maekawa, Motoko; Iwayama, Yoshimi; Ohnishi, Tetsuo; Toyoshima, Manabu; Shimamoto, Chie; Hisano, Yasuko; Toyota, Tomoko; Balan, Shabeesh; Matsuzaki, Hideo; Iwata, Yasuhide; Takagai, Shu; Yamada, Kohei; Ota, Motonori; Fukuchi, Satoshi; Okada, Yohei; Akamatsu, Wado; Tsujii, Masatsugu; Kojima, Nobuhiko; Owada, Yuji; Okano, Hideyuki; Mori, Norio; Yoshikawa, Takeo

2015-01-01

The solute carrier 27A (SLC27A) gene family encodes fatty acid transport proteins (FATPs) and includes 6 members. During fetal and postnatal periods of development, the growing brain requires a reliable supply of fatty acids. Because autism spectrum disorders (ASD) are now recognized as disorders caused by impaired early brain development, it is possible that functional abnormalities of SLC27A genes may contribute to the pathogenesis of ASD. Here, we confirmed the expression of SLC27A3 and SLC27A4 in human neural stem cells derived from human induced pluripotent stem cells, which suggested their involvement in the developmental stage of the central nervous system. Additionally, we resequenced the SLC27A3 and SLC27A4 genes using 267 ASD patient and 1140 control samples and detected 47 (44 novel and 29 nonsynonymous) and 30 (17 novel and 14 nonsynonymous) variants for the SLC27A3 and SLC27A4, respectively, revealing that they are highly polymorphic with multiple rare variants. The SLC27A4 Ser209 allele was more frequently represented in ASD samples. Furthermore, we showed that a SLC27A4 Ser209 mutant resulted in significantly higher fluorescently-labeled fatty acid uptake into bEnd3 cells, a mouse brain capillary-derived endothelial cell line, compared with SLC27A4 Gly209, suggesting that the functional change may contribute to ASD pathophysiology. PMID:26548558

Hair Cell Loss, Spiral Ganglion Degeneration, and Progressive Sensorineural Hearing Loss in Mice with Targeted Deletion of Slc44a2/Ctl2.

PubMed

Kommareddi, Pavan; Nair, Thankam; Kakaraparthi, Bala Naveen; Galano, Maria M; Miller, Danielle; Laczkovich, Irina; Thomas, Trey; Lu, Lillian; Rule, Kelli; Kabara, Lisa; Kanicki, Ariane; Hughes, Elizabeth D; Jones, Julie M; Hoenerhoff, Mark; Fisher, Susan G; Altschuler, Richard A; Dolan, David; Kohrman, David C; Saunders, Thomas L; Carey, Thomas E

2015-12-01

SLC44A2 (solute carrier 44a2), also known as CTL2 (choline transporter-like protein 2), is expressed in many supporting cell types in the cochlea and is implicated in hair cell survival and antibody-induced hearing loss. In mice with the mixed C57BL/6-129 background, homozygous deletion of Slc44a2 exons 3–10 (Slc44a2(Δ/Δ)resulted in high-frequency hearing loss and hair cell death. To reduce effects associated with age-related hearing loss (ARHL) in these strains, mice carrying the Slc44a2Δ allele were backcrossed to the ARHL-resistant FVB/NJ strain and evaluated after backcross seven(N7) (99 % FVB). Slc44a2(Δ/Δ) mice produced abnormally spliced Slc44a2 transcripts that contain a frame shift and premature stop codons. Neither full-length SLC44A2 nor a putative truncated protein could be detected in Slc44a2(Δ/Δ) mice, suggesting a likely null allele. Auditory brain stem responses (ABRs) of mice carrying the Slc44a2Δ allele on an FVB/NJ genetic background were tested longitudinally between the ages of 2 and 10 months. By 6 months of age,Slc44a2(Δ/Δ) mice exhibited hearing loss at 32 kHz,but at 12 and 24 kHz had sound thresholds similar to those of wild-type Slc44a2(+/+) and heterozygous +/Slc44a2Δ mice. After 6 months of age, Slc44a2(Δ/Δ) mutants exhibited progressive hearing loss at all frequencies and +/Slc44a2(Δ) mice exhibited moderate threshold elevations at high frequency. Histologic evaluation of Slc44a2(Δ/Δ) mice revealed extensive hair cell and spiral ganglion cell loss, especially in the basal turn of the cochlea. We conclude that Slc44a2 function is required for long-term hair cell survival and maintenance of hearing.

Conditionally Immortal Slc4a11−/− Mouse Corneal Endothelial Cell Line Recapitulates Disrupted Glutaminolysis Seen in Slc4a11−/− Mouse Model

PubMed Central

Zhang, Wenlin; Ogando, Diego G.; Kim, Edward T.; Choi, Moon-Jung; Li, Hongde; Tenessen, Jason M.; Bonanno, Joseph A.

2017-01-01

Purpose To establish conditionally immortal mouse corneal endothelial cell lines with genetically matched Slc4a11+/+ and Slc4a11−/− mice as a model for investigating pathology and therapies for SLC4A11 associated congenital hereditary endothelial dystrophy (CHED) and Fuchs' endothelial corneal dystrophy. Methods We intercrossed H-2Kb-tsA58 mice (Immortomouse) expressing an IFN-γ dependent and temperature-sensitive mutant of the SV40 large T antigen (tsTAg) with Slc4a11+/+ and Slc4a11−/− C57BL/6 mice. The growth characteristics of the cell lines was assessed by doubling time. Ion transport activities (Na+/H+ exchange, bicarbonate, lactate, and Slc4a11 ammonia transport) were analyzed by intracellular pH measurement. The metabolic status of the cell lines was assessed by analyzing TCA cycle intermediates via gas chromatography mass spectrometry (GC-MS). Results The immortalized Slc4a11+/+ and Slc4a11−/− mouse corneal endothelial cells (MCECs) remained proliferative through passage 49 and maintained similar active ion transport activity. As expected, proliferation was temperature sensitive and IFN-γ dependent. Slc4a11−/− MCECs exhibited decreased proliferative capacity, reduced NH3:H+ transport, altered expression of glutaminolysis enzymes similar to the Slc4a11−/− mouse, and reduced proportion of TCA cycle intermediates derived from glutamine with compensatory increases in glucose flux compared with Slc4a11+/+ MCECs. Conclusions This is the first report of the immortalization of MCECs. Ion transport of the immortalized endothelial cells remains active, except for NH3:H+ transporter activity in Slc4a11−/− MCECs. Furthermore, Slc4a11−/− MCECs recapitulate the glutaminolysis defects observed in Slc4a11−/− mouse corneal endothelium, providing an excellent tool to study the pathogenesis of SLC4A11 mutations associated with corneal endothelial dystrophies and to screen potential therapeutic agents. PMID:28738416

Sgr A* as Source of the Positrons Observed in the Galactic Center Region

NASA Astrophysics Data System (ADS)

Jean, Pierre; Guessoum, Nidhal; Ferrière, Katia

2017-01-01

We explore the possibility that a substantial fraction of the positrons observed to annihilate in the central region of our Galaxy come from the supermassive black hole Sgr A* that lies at the center. This idea was proposed by several authors, but the propagation of the emitted positrons into the bulge and beyond remained a serious problem for models of the origin of GC positrons. We assume models of positron production with different energies. The propagation of positrons from their production site is followed in detail with Monte-Carlo simulations, taking into account the physical conditions of the propagation regions as well as various physical interactions. Using the known physics of positron annihilation in astrophysical environments, we calculate the properties of the annihilation emission (time evolution and spatial distribution) for the different models under consideration. We present the results of these simulations and the conclusions/constraints that can be inferred from them.

Ultrashort megaelectronvolt positron beam generation based on laser-accelerated electrons

NASA Astrophysics Data System (ADS)

Xu, Tongjun; Shen, Baifei; Xu, Jiancai; Li, Shun; Yu, Yong; Li, Jinfeng; Lu, Xiaoming; Wang, Cheng; Wang, Xinliang; Liang, Xiaoyan; Leng, Yuxin; Li, Ruxin; Xu, Zhizhan

2016-03-01

Experimental generation of ultrashort MeV positron beams with high intensity and high density using a compact laser-driven setup is reported. A high-density gas jet is employed experimentally to generate MeV electrons with high charge; thus, a charge-neutralized MeV positron beam with high density is obtained during laser-accelerated electrons irradiating high-Z solid targets. It is a novel electron-positron source for the study of laboratory astrophysics. Meanwhile, the MeV positron beam is pulsed with an ultrashort duration of tens of femtoseconds and has a high peak intensity of 7.8 × 1021 s-1, thus allows specific studies of fast kinetics in millimeter-thick materials with a high time resolution and exhibits potential for applications in positron annihilation spectroscopy.

Astrophysical signatures of leptonium

NASA Astrophysics Data System (ADS)

Ellis, Simon C.; Bland-Hawthorn, Joss

2018-01-01

More than 1043 positrons annihilate every second in the centre of our Galaxy yet, despite four decades of observations, their origin is still unknown. Many candidates have been proposed, such as supernovae and low mass X-ray binaries. However, these models are difficult to reconcile with the distribution of positrons, which are highly concentrated in the Galactic bulge, and therefore require specific propagation of the positrons through the interstellar medium. Alternative sources include dark matter decay, or the supermassive black hole, both of which would have a naturally high bulge-to-disc ratio. The chief difficulty in reconciling models with the observations is the intrinsically poor angular resolution of gamma-ray observations, which cannot resolve point sources. Essentially all of the positrons annihilate via the formation of positronium. This gives rise to the possibility of observing recombination lines of positronium emitted before the atom annihilates. These emission lines would be in the UV and the NIR, giving an increase in angular resolution of a factor of 104 compared to gamma ray observations, and allowing the discrimination between point sources and truly diffuse emission. Analogously to the formation of positronium, it is possible to form atoms of true muonium and true tauonium. Since muons and tauons are intrinsically unstable, the formation of such leptonium atoms will be localised to their places of origin. Thus observations of true muonium or true tauonium can provide another way to distinguish between truly diffuse sources such as dark matter decay, and an unresolved distribution of point sources. Contribution to the Topical Issue "Low Energy Positron and Electron Interactions", edited by James Sullivan, Ron White, Michael Bromley, Ilya Fabrikant and David Cassidy.

Probing vacancy-type free-volume defects in Li2B4O7 single crystal by positron annihilation lifetime spectroscopy

NASA Astrophysics Data System (ADS)

Shpotyuk, O.; Adamiv, V.; Teslyuk, I.; Ingram, A.; Demchenko, P.

2018-01-01

Vacancy-type free-volume defects in lithium tetraborate Li2B4O7 single crystal, grown by the Czochralski technique, are probed with positron annihilation spectroscopy in the lifetime measuring mode. The experimental positron lifetime spectrum is reconstructed within the three-component fitting, involving channels of positron and positronium Ps trapping, as well as within the two-component fitting with a positronium-compensating source input. Structural configurations of the most efficient positron traps are considered using the crystallographic specificity of lithium tetraborate with the main accent on cation-type vacancies. Possible channels of positron trapping are visualized using the electronic structure calculations with density functional theory at the basis of structural parameters proper to Li2B4O7. Spatially-extended positron-trapping complexes involving singly-ionized lithium vacancies, with character lifetime close to 0.32 ns, are responsible for positron trapping in the nominally undoped lithium tetraborate Li2B4O7 crystal.

The PEPPo method for polarized positrons and PEPPo II

DOE PAGES

Cardman, Lawrence S.

2018-05-01

The Polarized Electrons for Polarized Positrons (PEPPo) experiment at the injector of the Continuous Electron Beam Accelerator Facility demonstrated for the first time the efficient transfer of polarization from electrons to positrons via a two-step process: polarized bremsstrahlung radiation is induced by a polarized electron beam in a high-Z target; then the polarized bremsstrahlung produces polarized positrons via the pair-production process in the same target. Positron polarization up to 82% was measured for an initial electron beam momentum of 8.19 MeV/c, limited only by the electron beam polarization of 85%. This technique extends polarized positron capabilities from GeV to MeVmore » electron beams, and opens access to polarized positron beam physics to a wide community. We present the results of the PEPPo experiment and outline tentative plans for a follow-up experiment that would investigate key aspects of an approach based on PEPPo as a polarized positron source for the 12 GeV Upgrade of CEBAF.« less

Surface and bulk investigations at the high intensity positron beam facility NEPOMUC

NASA Astrophysics Data System (ADS)

Hugenschmidt, C.; Dollinger, G.; Egger, W.; Kögel, G.; Löwe, B.; Mayer, J.; Pikart, P.; Piochacz, C.; Repper, R.; Schreckenbach, K.; Sperr, P.; Stadlbauer, M.

2008-10-01

The NEutron-induced POsitron source MUniCh (NEPOMUC) at the research reactor FRM II delivers a low-energy positron beam ( E = 15-1000 eV) of high intensity in the range between 4 × 10 7 and 5 × 10 8 moderated positrons per second. At present four experimental facilities are in operation at NEPOMUC: a coincident Doppler-broadening spectrometer (CDBS) for defect spectroscopy and investigations of the chemical vicinity of defects, a positron annihilation-induced Auger-electron spectrometer (PAES) for surface studies and an apparatus for the production of the negatively charged positronium ion Ps -. Recently, the pulsed low-energy positron system (PLEPS) has been connected to the NEPOMUC beam line, and first positron lifetime spectra were recorded within short measurement times. A positron remoderation unit which is operated with a tungsten single crystal in back reflection geometry has been implemented in order to improve the beam brilliance. An overview of NEPOMUC's status, experimental results and recent developments at the running spectrometers are presented.

Use of landsat ETM+ SLC-off segment-based gap-filled imagery for crop type mapping

USGS Publications Warehouse

Maxwell, S.K.; Craig, M.E.

2008-01-01

Failure of the Scan Line Corrector (SLC) on the Landsat ETM+ sensor has had a major impact on many applications that rely on continuous medium resolution imagery to meet their objectives. The United States Department of Agriculture (USDA) Cropland Data Layer (CDL) program uses Landsat imagery as the primary source of data to produce crop-specific maps for 20 states in the USA. A new method has been developed to fill the image gaps resulting from the SLC failure to support the needs of Landsat users who require coincident spectral data, such as for crop type mapping and monitoring. We tested the new gap-filled method for a CDL crop type mapping project in eastern Nebraska. Scan line gaps were simulated on two Landsat 5 images (spring and late summer 2003) and then gap-filled using landscape boundary models, or segment models, that were derived from 1992 and 2002 Landsat images (used in the gap-fill process). Various date combinations of original and gap-filled images were used to derive crop maps using a supervised classification process. Overall kappa values were slightly higher for crop maps derived from SLC-off gap-filled images compared to crop maps derived from the original imagery (0.3–1.3% higher). Although the age of the segment model used to derive the SLC-off gap-filled product did not negatively impact the overall agreement, differences in individual cover type agreement did increase (−0.8%–1.6% using the 2002 segment model to −5.0–5.1% using the 1992 segment model). Classification agreement also decreased for most of the classes as the size of the segment used in the gap-fill process increased.

THE GALACTIC POSITRON ANNIHILATION RADIATION AND THE PROPAGATION OF POSITRONS IN THE INTERSTELLAR MEDIUM

DOE Office of Scientific and Technical Information (OSTI.GOV)

Higdon, J. C.; Lingenfelter, R. E.; Rothschild, R. E.

2009-06-10

The ratio of the luminosity of diffuse 511 keV positron annihilation radiation, measured by INTEGRAL in its four years, from a Galactic 'positron bulge' (<1.5 kpc) compared to that of the disk is {approx}1.4. This ratio is roughly 4 times larger than that expected simply from the stellar bulge-to-disk ratio of {approx}0.33 of the Galactic supernovae (SNe), which are thought to be the principal source of the annihilating positrons through the decay of radionuclei made by explosive nucleosynthesis in the SNe. This large discrepancy has prompted a search for new sources. Here, however, we show that the measured 511 keVmore » luminosity ratio can be fully understood in the context of a Galactic SN origin when the differential propagation of these {approx} MeV positrons in the various phases of the interstellar medium is taken into consideration, since these relativistic positrons must first slow down to energies {<=}10 eV before they can annihilate. Moreover, without propagation, none of the proposed positron sources, new or old, can explain the two basic properties on the Galactic annihilation radiation: the fraction of the annihilation that occurs through positronium formation and the ratio of the broad/narrow components of the 511 keV line. In particular, we show that in the neutral phases of the interstellar medium, which fill most of the disk (>3.5 kpc), the cascade of the magnetic turbulence, which scatters the positrons, is damped by ion-neutral friction, allowing positrons to stream along magnetic flux tubes. We find that nearly 1/2 of the positrons produced in the disk escape from it into the halo. On the other hand, we show that within the extended, or interstellar, bulge (<3.5 kpc), essentially all of the positrons are born in the hot plasmas which fill that volume. We find that the diffusion mean free path is long enough that only a negligible fraction annihilate there and {approx}80% of them escape down into the H II and H I envelopes of molecular clouds that lie within 1.5 kpc before they slow down and annihilate, while the remaining {approx}20% escape out into the halo and the disk beyond. This propagation accounts for the low observed annihilation radiation luminosity of the disk compared to the bulge. In addition, we show that the primary annihilation sites of the propagating positrons in both the bulge and the disk are in the warm ionized phases of the interstellar medium. Such annihilation can also account for those two basic properties of the emission, the fraction ({approx}93% {+-} 7%) of annihilation via positronium and the ratio ({approx}0.5) of broad ({approx}5.4 keV) to narrow ({approx}1.3 keV) components of the bulge 511 keV line emission. Moreover, we expect that the bulk of this broad line emission comes from the tilted disk region (0.5 < R < 1.5 kpc) with a very large broad/narrow flux ratio of {approx}6, while much of the narrow line emission comes from the inner bulge (R < 0.5 kpc) with a negligible broad/narrow flux ratio. Separate spectral analyses of the 511 keV line emission from these two regions should be able to test this prediction, and further probe the structure of the interstellar medium. Lastly, we show that the asymmetry in the inner disk annihilation line flux, which has been suggested as added evidence for new sources, can also be fully understood from positron propagation and the asymmetry in the inner spiral arms as viewed from our solar perspective without any additional sources.« less

Drosophila SLC5A11 Mediates Hunger by Regulating K(+) Channel Activity.

PubMed

Park, Jin-Yong; Dus, Monica; Kim, Seonil; Abu, Farhan; Kanai, Makoto I; Rudy, Bernardo; Suh, Greg S B

2016-08-08

Hunger is a powerful drive that stimulates food intake. Yet, the mechanism that determines how the energy deficits that result in hunger are represented in the brain and promote feeding is not well understood. We previously described SLC5A11-a sodium/solute co-transporter-like-(or cupcake) in Drosophila melanogaster, which is required for the fly to select a nutritive sugar over a sweeter nonnutritive sugar after periods of food deprivation. SLC5A11 acts on approximately 12 pairs of ellipsoid body (EB) R4 neurons to trigger the selection of nutritive sugars, but the underlying mechanism is not understood. Here, we report that the excitability of SLC5A11-expressing EB R4 neurons increases dramatically during starvation and that this increase is abolished in the SLC5A11 mutation. Artificial activation of SLC5A11-expresssing neurons is sufficient to promote feeding and hunger-driven behaviors; silencing these neurons has the opposite effect. Notably, SLC5A11 transcript levels in the brain increase significantly when flies are starved and decrease shortly after starved flies are refed. Furthermore, expression of SLC5A11 is sufficient for promoting hunger-driven behaviors and enhancing the excitability of SLC5A11-expressing neurons. SLC5A11 inhibits the function of the Drosophila KCNQ potassium channel in a heterologous expression system. Accordingly, a knockdown of dKCNQ expression in SLC5A11-expressing neurons produces hunger-driven behaviors even in fed flies, mimicking the overexpression of SLC5A11. We propose that starvation increases SLC5A11 expression, which enhances the excitability of SLC5A11-expressing neurons by suppressing dKCNQ channels, thereby conferring the hunger state. Copyright © 2016 Elsevier Ltd. All rights reserved.

The evolutionary history and tissue mapping of amino acid transporters belonging to solute carrier families SLC32, SLC36, and SLC38.

PubMed

Sundberg, Björn E; Wååg, Elin; Jacobsson, Josefin A; Stephansson, Olga; Rumaks, Juris; Svirskis, Simons; Alsiö, Johan; Roman, Erika; Ebendal, Ted; Klusa, Vija; Fredriksson, Robert

2008-06-01

Members of the solute carrier families (SLC) 32, 36, and 38, together also designated the beta-group of SLCs, are known to transport neutral amino acids. In this paper, we show that these three families were present before the split of the animal lineage and that they are likely to share a common decent. We also show that the APF transporters found in plants are most likely homologous to the mammalian beta-group, suggesting that this type of transporters arouse early in the evolution of eukaryotes. We performed detailed tissue expression analysis of all the members of the beta-group in rat and found several examples of highly specific expression patterns, with SLC38A7 being exclusively found in liver, SLC38A5 in blood, and SLC38A4 in muscle and liver. Moreover, we found that SLC38A10 is expressed in several endocrine organs. We also found that SLC38A1 is highly up regulated in the cortex from rats treated with diazepam and that SLC38A2 is significantly down regulated in the same tissue. In addition, we performed a detailed expression analysis of SLC38A1 and SLC38A6 in mouse brain using in situ hybridization, which showed that both these transporters are widely expressed in the brain.

Account of the intratrack radiolytic processes for interpretation of the AMOC spectrum of liquid water

NASA Astrophysics Data System (ADS)

Zvezhinskiy, D. S.; Butterling, M.; Wagner, A.; Krause-Rehberg, R.; Stepanov, S. V.

2013-06-01

Recent development of the Gamma-induced Positron Spectroscopy (GiPS) setup significantly extends applicability of the Age-Momentum Correlation technique (AMOC) for studies of the bulk samples. It also provides many advantages comparing with conventional positron annihilation experiments in liquids, such as extremely low annihilation fraction in vessel walls, absence of a positron source and positron annihilations in it. We have developed a new approach for processing and interpretation of the AMOC-GiPS data based on the diffusion recombination model of the intratrack radiolytic processes. This approach is verified in case of liquid water, which is considered as a reference medium in the positron and positronium chemistry.

The Human SLC25A33 and SLC25A36 Genes of Solute Carrier Family 25 Encode Two Mitochondrial Pyrimidine Nucleotide Transporters*

PubMed Central

Di Noia, Maria Antonietta; Todisco, Simona; Cirigliano, Angela; Rinaldi, Teresa; Agrimi, Gennaro; Iacobazzi, Vito; Palmieri, Ferdinando

2014-01-01

The human genome encodes 53 members of the solute carrier family 25 (SLC25), also called the mitochondrial carrier family, many of which have been shown to transport inorganic anions, amino acids, carboxylates, nucleotides, and coenzymes across the inner mitochondrial membrane, thereby connecting cytosolic and matrix functions. Here two members of this family, SLC25A33 and SLC25A36, have been thoroughly characterized biochemically. These proteins were overexpressed in bacteria and reconstituted in phospholipid vesicles. Their transport properties and kinetic parameters demonstrate that SLC25A33 transports uracil, thymine, and cytosine (deoxy)nucleoside di- and triphosphates by an antiport mechanism and SLC25A36 cytosine and uracil (deoxy)nucleoside mono-, di-, and triphosphates by uniport and antiport. Both carriers also transported guanine but not adenine (deoxy)nucleotides. Transport catalyzed by both carriers was saturable and inhibited by mercurial compounds and other inhibitors of mitochondrial carriers to various degrees. In confirmation of their identity (i) SLC25A33 and SLC25A36 were found to be targeted to mitochondria and (ii) the phenotypes of Saccharomyces cerevisiae cells lacking RIM2, the gene encoding the well characterized yeast mitochondrial pyrimidine nucleotide carrier, were overcome by expressing SLC25A33 or SLC25A36 in these cells. The main physiological role of SLC25A33 and SLC25A36 is to import/export pyrimidine nucleotides into and from mitochondria, i.e. to accomplish transport steps essential for mitochondrial DNA and RNA synthesis and breakdown. PMID:25320081

The Physiopathological Role of the Exchangers Belonging to the SLC37 Family

NASA Astrophysics Data System (ADS)

Cappello, Anna Rita; Curcio, Rosita; Lappano, Rosamaria; Maggiolini, Marcello; Dolce, Vincenza

2018-04-01

The human SLC37 gene family includes four proteins SLC37A1-4, localized in the endoplasmic reticulum (ER) membrane. They have been grouped into the SLC37 family due to their sequence homology to the bacterial organophosphate/phosphate (Pi) antiporter. SLC37A1-3 are the less characterized isoforms. SLC37A1 and SLC37A2 are Pi-linked glucose-6-phosphate (G6P) antiporters, catalyzing both homologous (Pi/Pi) and heterologous (G6P/Pi) exchanges, whereas SLC37A3 transport properties remain to be clarified. Furthermore, SLC37A1 is highly homologous to the bacterial glycerol 3-phosphate permeases, so it is supposed to transport also glycerol-3-phosphate. The physiological role of SLC37A1-3 is yet to be further investigated. SLC37A1 seems to be required for lipid biosynthesis in cancer cell lines, SLC37A2 has been proposed as a vitamin D and a phospho-progesterone receptor target gene, while mutations in the SLC37A3 gene appear to be associated with congenital hyperinsulinism of infancy. SLC37A4, also known as glucose-6-phosphate translocase (G6PT), transports G6P from the cytoplasm into the ER lumen, working in complex with either glucose-6-phosphatase-α (G6Pase-α) or G6Pase-β to hydrolyze intraluminal G6P to Pi and glucose. G6PT and G6Pase-β are ubiquitously expressed, whereas G6Pase-α is specifically expressed in the liver, kidney and intestine. G6PT/G6Pase-α complex activity regulates fasting blood glucose levels, whereas G6PT/G6Pase-β is required for neutrophil functions. G6PT deficiency is responsible for glycogen storage disease type Ib (GSD-Ib), an autosomal recessive disorder associated with both defective metabolic and myeloid phenotypes. Several kinds of mutations have been identified in the SLC37A4 gene, affecting G6PT function. An increased autoimmunity risk for GSD-Ib patients has also been reported, moreover, SLC37A4 seems to be involved in autophagy.

Summary of experimental studies, at CERN, on a positron source using crystal effects

NASA Astrophysics Data System (ADS)

Artru, X.; Baier, V.; Beloborodov, K.; Bogdanov, A.; Bukin, A.; Burdin, S.; Chehab, R.; Chevallier, M.; Cizeron, R.; Dauvergne, D.; Dimova, T.; Druzhinin, V.; Dubrovin, M.; Gatignon, L.; Golubev, V.; Jejcic, A.; Keppler, P.; Kirsch, R.; Kulibaba, V.; Lautesse, Ph.; Major, J.; Poizat, J.-C.; Potylitsin, A.; Remillieux, J.; Serednyakov, S.; Shary, V.; Strakhovenko, V.; Sylvia, C.

2005-11-01

A new kind of positron sources for future linear colliders, where the converter is an aligned tungsten crystal, oriented on the <1 1 1>-axis, has been studied at CERN in the WA103 experiment with tertiary electron beams from the SPS. In such sources the photons resulting from channeling radiation and coherent bremsstrahlung create the e+e- pairs. Electron beams, of 6 and 10 GeV, were impinging on different kinds of targets: a 4 mm thick crystal, a 8 mm thick crystal and a compound target made of 4 mm crystal followed by 4 mm amorphous disk. An amorphous tungsten target 20 mm thick was also used for the sake of comparison with the 8 mm crystal and to check the ability of the detection system to provide the correct track reconstruction. The charged particles coming out from the target were detected in a drift chamber immersed partially in a magnetic field. The reconstruction of the particle trajectories provided the energy and angular spectrum of the positrons in a rather wide energy range (up to 150 MeV) and angular domain (up to 30°). The experimental approach presented in this article provides a full description of this kind of source. A presentation of the measured positron distribution in momentum space (longitudinal versus transverse) is given to allow an easy determination of the available yield for a given momentum acceptance. Results on photons, measured downstream of the positron detector, are also presented. A significant enhancement of photon and positron production is clearly observed. This enhancement, for a 10 GeV incident beam, is of 4 for the 4 mm thick crystal and larger than 2 for the 8 mm thick crystal. Another important result concerns the validation of the simulations for the crystals, for which a quite good agreement was met between the simulations and the experiment, for positrons as well as for photons. These results are presented after a short presentation of the experimental setup and of the track reconstruction procedure.

Ultrashort megaelectronvolt positron beam generation based on laser-accelerated electrons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, Tongjun; Shen, Baifei, E-mail: bfshen@mail.shcnc.ac.cn; Xu, Jiancai, E-mail: jcxu@siom.ac.cn

Experimental generation of ultrashort MeV positron beams with high intensity and high density using a compact laser-driven setup is reported. A high-density gas jet is employed experimentally to generate MeV electrons with high charge; thus, a charge-neutralized MeV positron beam with high density is obtained during laser-accelerated electrons irradiating high-Z solid targets. It is a novel electron–positron source for the study of laboratory astrophysics. Meanwhile, the MeV positron beam is pulsed with an ultrashort duration of tens of femtoseconds and has a high peak intensity of 7.8 × 10{sup 21} s{sup −1}, thus allows specific studies of fast kinetics in millimeter-thick materials withmore » a high time resolution and exhibits potential for applications in positron annihilation spectroscopy.« less

Quadrupole Alignment and Trajectory Correction for Future Linear Colliders: SLC Tests of a Dispersion-Free Steering Algorithm

DOE Office of Scientific and Technical Information (OSTI.GOV)

Assmann, R

2004-06-08

The feasibility of future linear colliders depends on achieving very tight alignment and steering tolerances. All proposals (NLC, JLC, CLIC, TESLA and S-BAND) currently require a total emittance growth in the main linac of less than 30-100% [1]. This should be compared with a 100% emittance growth in the much smaller SLC linac [2]. Major advances in alignment and beam steering techniques beyond those used in the SLC are necessary for the next generation of linear colliders. In this paper, we present an experimental study of quadrupole alignment with a dispersion-free steering algorithm. A closely related method (wakefield-free steering) takesmore » into account wakefield effects [3]. However, this method can not be studied at the SLC. The requirements for future linear colliders lead to new and unconventional ideas about alignment and beam steering. For example, no dipole correctors are foreseen for the standard trajectory correction in the NLC [4]; beam steering will be done by moving the quadrupole positions with magnet movers. This illustrates the close symbiosis between alignment, beam steering and beam dynamics that will emerge. It is no longer possible to consider the accelerator alignment as static with only a few surveys and realignments per year. The alignment in future linear colliders will be a dynamic process in which the whole linac, with thousands of beam-line elements, is aligned in a few hours or minutes, while the required accuracy of about 5 pm for the NLC quadrupole alignment [4] is a factor of 20 higher than in existing accelerators. The major task in alignment and steering is the accurate determination of the optimum beam-line position. Ideally one would like all elements to be aligned along a straight line. However, this is not practical. Instead a ''smooth curve'' is acceptable as long as its wavelength is much longer than the betatron wavelength of the accelerated beam. Conventional alignment methods are limited in accuracy by errors in the survey and the fiducials. Beam-based alignment methods ideally only depend upon the BPM resolution and generally provide much better precision. Many of those techniques are described in other contributions to this workshop. In this paper we describe our experiences with a dispersion-free steering algorithm for linacs. This algorithm was first suggested by Raubenheimer and Ruth in 1990 [5]. It h as been studied in simulations for NLC [5], TESLA [6], the S-BAND proposal [7] and CLIC [8]. The dispersion-free steering technique can be applied to the whole linac at once and returns the alignment (or trajectory) that minimizes the dispersive emittance growth of the beam. Thus it allows an extremely fast alignment of the beam-line. As we will show dispersion-free steering is only sensitive to quadrupole misalignments. Wakefield-free steering [3] as mentioned before is a closely related technique that minimizes the emittance growth caused by both dispersion and wakefields. Due to hardware limitations (i.e. insufficient relative range of power supplies) we could not study this method experimentally in the SLC. However, its systematics are very similar to those of dispersion-free steering. The studies of dispersion-free steering which are presented made extensive use of the unique potential of the SLC as the only operating linear collider. We used it to study the performance and problems of advanced beam-based optimization tools in a real beam-line environment and on a large scale. We should mention that the SLC has utilized beam-based alignment for years [9], using the difference of electron and positron trajectories. This method, however, cannot be used in future linear colliders. The goal of our work is to demonstrate the performance of advanced beam-based alignment techniques in linear colliders and to anticipate possible reality-related problems. Those can then be solved in the design state for the next generation of linear colliders.« less

Cosmic Ray Positrons from Pulsars

NASA Technical Reports Server (NTRS)

Harding, Alice K.

2010-01-01

Pulsars are potential Galactic sources of positrons through pair cascades in their magnetospheres. There are, however, many uncertainties in establishing their contribution to the local primary positron flux. Among these are the local density of pulsars, the cascade pair multiplicities that determine the injection rate of positrons from the pulsar, the acceleration of the injected particles by the pulsar wind termination shock, their rate of escape from the pulsar wind nebula, and their propagation through the interstellar medium. I will discuss these issues in the context of what we are learning from the new Fermi pulsar detections and discoveries.

The novel putative bile acid transporter SLC10A5 is highly expressed in liver and kidney

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fernandes, Carla F.; Godoy, Jose R.; Doering, Barbara

2007-09-14

Here we report the identification, cloning, and characterization of SLC10A5, which is a new member of Solute Carrier Family 10 (SLC10), also known as the 'sodium/bile acid cotransporter family'. Expression of SLC10A5/Slc10a5 was examined by quantitative real-time PCR and revealed its highest expression levels in liver and kidney in humans, rat and mouse. In rat liver and kidney, Slc10a5 expression was localized by in situ hybridization to hepatocytes and proximal tubules, respectively. A SLC10A5-FLAG fusion protein was expressed in HEK293 cells and showed an apparent molecular weight of 42 kDa after immunoprecipitation. When expressed in Xenopus laevis oocytes, the SLC10A5-FLAGmore » protein was detected in the oocyte's plasma membrane but showed no transport activity for taurocholate, cholate, estrone-3-sulfate, or dehydroepiandrosterone sulfate. As bile acid carriers are the most related carriers to SLC10A5 though, we strongly suppose that SLC10A5 is an orphan carrier with yet non-identified substrates.« less

Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice

PubMed Central

Corpe, Christopher P.; Tu, Hongbin; Eck, Peter; Wang, Jin; Faulhaber-Walter, Robert; Schnermann, Jurgen; Margolis, Sam; Padayatty, Sebastian; Sun, He; Wang, Yaohui; Nussbaum, Robert L.; Espey, Michael Graham; Levine, Mark

2010-01-01

Levels of the necessary nutrient vitamin C (ascorbate) are tightly regulated by intestinal absorption, tissue accumulation, and renal reabsorption and excretion. Ascorbate levels are controlled in part by regulation of transport through at least 2 sodium-dependent transporters: Slc23a1 and Slc23a2 (also known as Svct1 and Svct2, respectively). Previous work indicates that Slc23a2 is essential for viability in mice, but the roles of Slc23a1 for viability and in adult physiology have not been determined. To investigate the contributions of Slc23a1 to plasma and tissue ascorbate concentrations in vivo, we generated Slc23a1–/– mice. Compared with wild-type mice, Slc23a1–/– mice increased ascorbate fractional excretion up to 18-fold. Hepatic portal ascorbate accumulation was nearly abolished, whereas intestinal absorption was marginally affected. Both heterozygous and knockout pups born to Slc23a1–/– dams exhibited approximately 45% perinatal mortality, and this was associated with lower plasma ascorbate concentrations in dams and pups. Perinatal mortality of Slc23a1–/– pups born to Slc23a1–/– dams was prevented by ascorbate supplementation during pregnancy. Taken together, these data indicate that ascorbate provided by the dam influenced perinatal survival. Although Slc23a1–/– mice lost as much as 70% of their ascorbate body stores in urine daily, we observed an unanticipated compensatory increase in ascorbate synthesis. These findings indicate a key role for Slc23a1 in renal ascorbate absorption and perinatal survival and reveal regulation of vitamin C biosynthesis in mice. PMID:20200446

The human SLC25A33 and SLC25A36 genes of solute carrier family 25 encode two mitochondrial pyrimidine nucleotide transporters.

PubMed

Di Noia, Maria Antonietta; Todisco, Simona; Cirigliano, Angela; Rinaldi, Teresa; Agrimi, Gennaro; Iacobazzi, Vito; Palmieri, Ferdinando

2014-11-28

The human genome encodes 53 members of the solute carrier family 25 (SLC25), also called the mitochondrial carrier family, many of which have been shown to transport inorganic anions, amino acids, carboxylates, nucleotides, and coenzymes across the inner mitochondrial membrane, thereby connecting cytosolic and matrix functions. Here two members of this family, SLC25A33 and SLC25A36, have been thoroughly characterized biochemically. These proteins were overexpressed in bacteria and reconstituted in phospholipid vesicles. Their transport properties and kinetic parameters demonstrate that SLC25A33 transports uracil, thymine, and cytosine (deoxy)nucleoside di- and triphosphates by an antiport mechanism and SLC25A36 cytosine and uracil (deoxy)nucleoside mono-, di-, and triphosphates by uniport and antiport. Both carriers also transported guanine but not adenine (deoxy)nucleotides. Transport catalyzed by both carriers was saturable and inhibited by mercurial compounds and other inhibitors of mitochondrial carriers to various degrees. In confirmation of their identity (i) SLC25A33 and SLC25A36 were found to be targeted to mitochondria and (ii) the phenotypes of Saccharomyces cerevisiae cells lacking RIM2, the gene encoding the well characterized yeast mitochondrial pyrimidine nucleotide carrier, were overcome by expressing SLC25A33 or SLC25A36 in these cells. The main physiological role of SLC25A33 and SLC25A36 is to import/export pyrimidine nucleotides into and from mitochondria, i.e. to accomplish transport steps essential for mitochondrial DNA and RNA synthesis and breakdown. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

2. AERIAL VIEW OF SLC3 FROM THE NORTH. SLC3W IN ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

2. AERIAL VIEW OF SLC-3 FROM THE NORTH. SLC-3W IN FOREGROUND; SLC-3E IN BACKGROUND. LAUNCH OPERATIONS BUILDING (LOB; BLDG. 763) AND CABLE TRAYS BETWEEN LOB AND THE PADS VISIBLE IMMEDIATELY EAST (LEFT) OF THE PADS. VEHICLE SUPPORT BUILDING (BLDG. 766) LOCATED EAST OF ROAD IN LEFT FOREGROUND. TECHNICAL SUPPORT BUILDING (BLDG. 762/762A) AND SLC-3 AIR FORCE BUILDING (BLDG. 761) VISIBLE EAST OF LOG IN LEFT BACKGROUND. - Vandenberg Air Force Base, Space Launch Complex 3, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

Fine Mapping and Functional Analysis Reveal a Role of SLC22A1 in Acylcarnitine Transport.

PubMed

Kim, Hye In; Raffler, Johannes; Lu, Wenyun; Lee, Jung-Jin; Abbey, Deepti; Saleheen, Danish; Rabinowitz, Joshua D; Bennett, Michael J; Hand, Nicholas J; Brown, Christopher; Rader, Daniel J

2017-10-05

Genome-wide association studies have identified a signal at the SLC22A1 locus for serum acylcarnitines, intermediate metabolites of mitochondrial oxidation whose plasma levels associate with metabolic diseases. Here, we refined the association signal, performed conditional analyses, and examined the linkage structure to find coding variants of SLC22A1 that mediate independent association signals at the locus. We also employed allele-specific expression analysis to find potential regulatory variants of SLC22A1 and demonstrated the effect of one variant on the splicing of SLC22A1. SLC22A1 encodes a hepatic plasma membrane transporter whose role in acylcarnitine physiology has not been described. By targeted metabolomics and isotope tracing experiments in loss- and gain-of-function cell and mouse models of Slc22a1, we uncovered a role of SLC22A1 in the efflux of acylcarnitines from the liver to the circulation. We further validated the impacts of human variants on SLC22A1-mediated acylcarnitine efflux in vitro, explaining their association with serum acylcarnitine levels. Our findings provide the detailed molecular mechanisms of the GWAS association for serum acylcarnitines at the SLC22A1 locus by functionally validating the impact of SLC22A1 and its variants on acylcarnitine transport. Copyright © 2017. Published by Elsevier Inc.

SLC7 family transporters control the establishment of left-right asymmetry during organogenesis in medaka by activating mTOR signaling.

PubMed

Asaoka, Yoichi; Nagai, Yoko; Namae, Misako; Furutani-Seiki, Makoto; Nishina, Hiroshi

2016-05-20

The precise government of the left-right (LR) specification of an organ is an essential aspect of its morphogenesis. Multiple signaling cascades have been implicated in the establishment of vertebrate LR asymmetry. Recently, mTOR signaling was found to critically regulate the development of LR asymmetry in zebrafish. However, the upstream factor(s) that activate mTOR signaling in the context of LR specification are as yet unknown. In this study, we identify the SLC7 amino acid transporters Slc7a7 and Slc7a8 as novel regulators of LR asymmetry development in the small fish medaka. Knockdown of Slc7a7 and/or Slc7a8 in medaka embryos disrupted LR organ asymmetries. Depletion of Slc7a7 hindered left-sided expression of the southpaw (spaw) gene, which is responsible for LR axis determination. Work at the cellular level revealed that Slc7a7 coordinates ciliogenesis in the epithelium of Kupffer's vesicle and thereby the generation of the nodal fluid flow required for LR asymmetry. Interestingly, knockdown of Slc7a7 depressed mTOR signaling activity in medaka embryos. Treatment with rapamycin, an inhibitor of mTOR signaling, together with Slc7a7 knockdown synergistically perturbed spaw expression, indicating an interaction between Slc7a7 and mTOR signaling affecting gene expression required for LR specification. Taken together, our results demonstrate that Slc7a7 governs the regulation of LR asymmetry development via the activation of mTOR signaling. Copyright © 2016 Elsevier Inc. All rights reserved.

Variants in Solute Carrier SLC26A9 Modify Prenatal Exocrine Pancreatic Damage in Cystic Fibrosis

PubMed Central

Miller, Melissa R.; Soave, David; Li, Weili; Gong, Jiafen; Pace, Rhonda G.; Boëlle, Pierre-Yves; Cutting, Garry R.; Drumm, Mitchell L.; Knowles, Michael R.; Sun, Lei; Rommens, Johanna M.; Accurso, Frank; Durie, Peter R.; Corvol, Harriet; Levy, Hara; Sontag, Marci K.; Strug, Lisa J.

2015-01-01

Objectives To test the hypothesis that multiple constituents of the apical plasma membrane residing alongside the causal CF Transmembrane Conductance Regulator (CFTR) protein, including known cystic fibrosis (CF) modifiers SLC26A9, SLC6A14, and SLC9A3, would be associated with prenatal exocrine pancreatic damage as measured by newborn screened (NBS) IRT levels. Study design NBS IRT measures and genome-wide genotype data were available on 111 subjects from Colorado, 37 subjects from Wisconsin, and 80 subjects from France. Multiple linear regression was used to determine whether any of eight SNPs in SLC26A9, SLC6A14 and SLC9A3 were associated with IRT and whether other constituents of the apical plasma membrane contributed to IRT. Results In the Colorado sample, three SLC26A9 SNPs were associated with NBS IRT (min P = 1.16 × 10−3; rs7512462), but no SLC6A14 or SLC9A3 SNPs were associated (P > 0.05). The rs7512462 association replicated in the Wisconsin sample (P = 0.03) but not in the French sample (P = 0.76). Furthermore, rs7512462 was the top ranked apical membrane constituent in the combined Colorado and Wisconsin sample. Conclusions NBS IRT is a biomarker of prenatal exocrine pancreatic disease in patients with CF, and a SNP in SLC26A9 accounts for significant IRT variability. This suggests SLC26A9 as a potential therapeutic target to ameliorate exocrine pancreatic disease. PMID:25771386

Status and Perspectives for a Slow Positron Beam Facility at the HH—NIPNE Bucharest

NASA Astrophysics Data System (ADS)

Constantin, Florin; Craciun, Liviu Stefan; Constantinescu, Olimpiu; Ghita, Ionica Alina; Ionescu, Cristina; Racolta, Petru Mihai; Straticiuc, Mihai; Vasilescu, Angela; Braic, Viorel; Zoita, Catalin; Kiss, Adrian; Bojin, Dionezie

2009-03-01

The development of a positron annihilation spectroscopy laboratory at the HH-NIPNE Bucharest-to be used for material studies and applications was started in the last 10 years. In the framework of a national research project extended over the last 3 years, was designed a low energy positron accelerator, as a high-vacuum dedicated beam line with two options: a 25 mCi 22NaCl source and in line with the NIPNE-cyclotron or a new intense compact cyclotron. The construction of the beam line was planned as a sequence of modules: source- moderator system; magnetical filter for fast positrons in order to select the positrons energies in the range 0.8-1 keV; a modular system for focusing, transport and acceleration of monoenergetic positrons in the energy range 0.8-50 keV and a CDBS analysis chamber. The moderator proposed—is tungsten as a foil of about 3 μm prepared at the Optoelectronics Institute were put into a thermal treatment vacuum chamber and bombarded with electrons from a 100 W electron gun After the treatment, they were tested for changes of elemental composition of the surface and structure at the Polytechnic University. The structure tests were performed on a DRON 3 M diffractometer, with a Co tube (λKα = 1.7903 A)—the angular regions studied were around 34° (1 0 0) and 69° (2 0 0). In the present time, the trajectories of the positron are going to be simulated with dedicated software (an ion and electron optics simulator). For the coincidence measurements (CDBS) set-up we used a home-made 22NaCl source, by separation without carrier from a metallic Mg target irradiated with 12 MeV protons and separated by columnar cation exchange. A home- made biparametric system for CDBS measurements will be reported, also.

Status and Perspectives for a Slow Positron Beam Facility at the HH-NIPNE Bucharest

NASA Astrophysics Data System (ADS)

Straticiuc, Mihai; Craciun, Liviu Stefan; Constantinescu, Olimpiu; Ghita, Ionica Alina; Ionescu, Cristina; Racolta, Petru Mihai; Vasilescu, Angela; Braic, Viorel; Zoita, Catalin; Kiss, Adrian; Bojin, Dionezie

2009-03-01

The development of a positron annihilation spectroscopy laboratory at the HH-NIPNE Bucharest-to be used for material studies and applications was started in the last 10 years. In the framework of a national research project extended over the last 3 years, was designed a low energy positron accelerator, as a high-vacuum dedicated beam line with two options: a 25 mCi 22NaCl source and in line with the NIPNE-cyclotron or a new intense compact cyclotron. The construction of the beam line was planned as a sequence of modules: source- moderator system; magnetical filter for fast positrons in order to select the positrons energies in the range 0.8-1 keV; a modular system for focusing, transport and acceleration of monoenergetic positrons in the energy range 0.8-50 keV and a CDBS analysis chamber. The moderator proposed-is tungsten as a foil of about 3 μm prepared at the Optoelectronics Institute were put into a thermal treatment vacuum chamber and bombarded with electrons from a 100 W electron gun After the treatment, they were tested for changes of elemental composition of the surface and structure at the Polytechnic University. The structure tests were performed on a DRON 3 M diffractometer, with a Co tube (λKα = 1.7903 A)-the angular regions studied were around 34° (1 0 0) and 69° (2 0 0). In the present time, the trajectories of the positron are going to be simulated with dedicated software (an ion and electron optics simulator). For the coincidence measurements (CDBS) set-up we used a home-made 22NaCl source, by separation without carrier from a metallic Mg target irradiated with 12 MeV protons and separated by columnar cation exchange. A home- made biparametric system for CDBS measurements will be reported, also.

Development of a Simple Positron Age-Momentum Setup

NASA Astrophysics Data System (ADS)

Sheffield, Thomas; Quarles, C. A.

2009-04-01

A positron age-momentum setup that uses NIM Bin electronic modules and a conventional multichannel analyzer (MCA) is described. The essential idea is to accumulate a Doppler broadened spectrum (sensitive to the annihilation electron momentum) using a high purity Germanium detector in coincidence with a BaF2 scintillation counter, which also serves as the stop signal in a conventional positron lifetime setup. The MCA that collects the Doppler spectrum is gated by a selected region of the lifetime spectrum. Thus we can obtain Doppler broadening spectra as a function of positron lifetime: an age-momentum spectrum. The apparatus has been used so far to investigate a ZnO sample where the size of different vacancy trapping sites may affect the positron lifetime and the Doppler broadening spectrum. We are also looking at polymer and rubber carbon-black composite samples where differences in the Doppler spectrum may arise from positron trapping or positronium formation in the samples. Correction for background and contribution from the positron source itself to the Doppler spectrum will be discussed.

Apparatus for the analysis of surfaces in gas environments using Positron Spectroscopy

NASA Astrophysics Data System (ADS)

Satyal, Suman; Lim, Lawrence; Joglekar, Vibek; Kalaskar, Sushant; Shastry, Karthik; Weiss, Alex

2010-10-01

Positron spectroscopy performed with low energy beams can provide highly surface specific information due to the trapping of positrons in an image potential surface state at the time of annihilation. Here we describe a spectrometer that will employ differential pumping to enable us to transport the positrons most of the way from the source to the sample under high vacuum and then to traverse a thin gas layer surrounding the sample. The positrons will be implanted into the sample at energies less than ˜10 keV ensuring that a large fraction will diffuse back to the surface before annihilation. The Elemental content of the surface interacting with the gas environment will then be determined from the Doppler broadened gamma spectra. This system will include a time of flight positron annihilation induced Auger spectrometer (TOF-PAES) which correlates with the Doppler measurements at lower pressures.

A novel source of MeV positron bunches driven by energetic protons for PAS application

NASA Astrophysics Data System (ADS)

Tan, Zongquan; Xu, Wenzhen; Liu, Yanfen; Xiao, Ran; Kong, Wei; Ye, Bangjiao

2014-11-01

This paper proposes a novel methodology of MeV positrons generation for PAS application. Feasibility of this proposal analyzed by G4Beamline and Transport have shown reasonable success. Using 2 Hz, 1.6 GeV, 100 ns and 1.5 μC/bunch proton bunches for bombarding a graphite target, about 100 ns e+ bunches are generated. Quasi-monochromatic positrons in the range of 1-10 MeV included in these bunches have a flux of >107/s, peak brightness of 1014/s. A magnetic-confinement beamline is utilized to transport the positrons and a "Fast Beam Chopper" is unprecedentedly extended to chop those relativistic bunches. The positron beam can be finally characterized by the energy range of 1-10 MeV and bunch width from one hundred ps up to 1 ns. Such ultrashort bunches can be useful in tomography-type positron annihilation spectroscopy (PAS) as well as other applications.

Origin of the positron excess in cosmic rays.

PubMed

Blasi, Pasquale

2009-07-31

We show that the positron excess measured by the PAMELA experiment in the region between 10 and 100 GeV may well be a natural consequence of the standard scenario for the origin of Galactic cosmic rays. The "excess" arises because of positrons created as secondary products of hadronic interactions inside the sources, but the crucial physical ingredient which leads to a natural explanation of the positron flux is the fact that the secondary production takes place in the same region where cosmic rays are being accelerated. Therefore secondary positrons (and electrons) participate in the acceleration process and turn out to have a very flat spectrum, which is responsible, after propagation in the Galaxy, for the observed positron excess. This effect cannot be avoided though its strength depends on the values of the environmental parameters during the late stages of evolution of supernova remnants.

Search for Cosmic-Ray Electron and Positron Anisotropies with Seven Years of Fermi Large Area Telescope Data.

PubMed

Abdollahi, S; Ackermann, M; Ajello, M; Albert, A; Atwood, W B; Baldini, L; Barbiellini, G; Bellazzini, R; Bissaldi, E; Bloom, E D; Bonino, R; Bottacini, E; Brandt, T J; Bruel, P; Buson, S; Caragiulo, M; Cavazzuti, E; Chekhtman, A; Ciprini, S; Costanza, F; Cuoco, A; Cutini, S; D'Ammando, F; de Palma, F; Desiante, R; Digel, S W; Di Lalla, N; Di Mauro, M; Di Venere, L; Donaggio, B; Drell, P S; Favuzzi, C; Focke, W B; Fukazawa, Y; Funk, S; Fusco, P; Gargano, F; Gasparrini, D; Giglietto, N; Giordano, F; Giroletti, M; Green, D; Guiriec, S; Harding, A K; Jogler, T; Jóhannesson, G; Kamae, T; Kuss, M; Larsson, S; Latronico, L; Li, J; Longo, F; Loparco, F; Lubrano, P; Magill, J D; Malyshev, D; Manfreda, A; Mazziotta, M N; Meehan, M; Michelson, P F; Mitthumsiri, W; Mizuno, T; Moiseev, A A; Monzani, M E; Morselli, A; Negro, M; Nuss, E; Ohsugi, T; Omodei, N; Paneque, D; Perkins, J S; Pesce-Rollins, M; Piron, F; Pivato, G; Principe, G; Rainò, S; Rando, R; Razzano, M; Reimer, A; Reimer, O; Sgrò, C; Simone, D; Siskind, E J; Spada, F; Spandre, G; Spinelli, P; Strong, A W; Tajima, H; Thayer, J B; Torres, D F; Troja, E; Vandenbroucke, J; Zaharijas, G; Zimmer, S

2017-03-03

The Large Area Telescope on board the Fermi Gamma-ray Space Telescope has collected the largest ever sample of high-energy cosmic-ray electron and positron events since the beginning of its operation. Potential anisotropies in the arrival directions of cosmic-ray electrons or positrons could be a signature of the presence of nearby sources. We use almost seven years of data with energies above 42 GeV processed with the Pass 8 reconstruction. The present data sample can probe dipole anisotropies down to a level of 10^{-3}. We take into account systematic effects that could mimic true anisotropies at this level. We present a detailed study of the event selection optimization of the cosmic-ray electrons and positrons to be used for anisotropy searches. Since no significant anisotropies have been detected on any angular scale, we present upper limits on the dipole anisotropy. The present constraints are among the strongest to date probing the presence of nearby young and middle-aged sources.

The choline transporter-like family SLC44: properties and roles in human diseases.

PubMed

Traiffort, Elisabeth; O'Regan, Seana; Ruat, Martial

2013-01-01

The Na(+)-independent, high affinity choline carrier system proposed to supply choline for the synthesis of cell membrane phospholipids was recently associated with SLC44 family members (SLC44A1-5) also called choline-like transporter family. SLC44A1 is widely expressed throughout the nervous system in both neurons and oligodendrocytes, while SLC44A2-4 are mainly detected in peripheral tissues. The subcellular localization of the proteins was mainly addressed for SLC44A1 through the development of specific antibodies. SLC44A1 is detected in both the plasma and mitochondrial membranes where the protein is able to transport choline at high affinity and in a Na(+)-independent manner. The physiological relevance of SLC44A1 as a choline carrier is indicated by its likely involvement in membrane synthesis for cell growth or repair, and also by its role in phospholipid production for the generation of lung surfactant. Moreover, an autoimmune disease has been related to the blockade of SLC44A2 function, which results in the alteration of hair cells in the inner ear and leads to autoimmune hearing loss. In the alloimmune syndrome called transfusion-related acute lung injury, antibodies to SLC44A2 cause a deleterious aggregation of granulocytes. Therefore transporters of the SLC44 family represent attractive and promising targets for therapeutic and diagnostic applications regarding both immune and degenerative diseases. Copyright © 2012 Elsevier Ltd. All rights reserved.

Interaction of atorvastatin with the human glial transporter SLC16A1.

PubMed

Sasaki, Shotaro; Futagi, Yuya; Ideno, Masaya; Kobayashi, Masaki; Narumi, Katsuya; Furugen, Ayako; Iseki, Ken

2016-10-05

Solute carrier (SLC) 16A1 is a pH-dependent carrier of 5-oxoproline, a derivative of the amino acid. SLC16A1 interacts with carboxylate group-containing substrates, which are also present in atorvastatin, and might be the reason for its ability to interact with atorvastatin. Does atorvastatin interact with the carrier? Does it also interact with the carrier via the substrate recognition site? This study was carried out to answer these questions. Polymerase chain reaction was used to determine the expression of SLC16A1 in normal human astrocytes. We induced SLC16A1 expression in a mammalian cell line and in Xenopus laevis oocytes. We used [(3)H] 5-oxoproline for direct measurement of SLC16A1-specific transport activity. SLC16A1 was clearly observed in normal human astrocytes. 3-Hydroxy-3-methyl-glutaryl-CoA reductase inhibitors inhibited the SLC16A1-specific transport of 5-oxoproline. Atorvastatin was the most potent inhibitor, with an inhibition constant of 40μM. The drug was a non-competitive inhibitor of SLC16A1. In the present study, we showed non-competitive inhibition of SLC16A1-specific transport activity by atorvastatin. However, the affinity between the drug and the carrier was extremely low. Therefore, the interaction of atorvastatin with SLC16A1 is unlikely to be a problem in clinical practice. Copyright © 2016. Published by Elsevier B.V.

Butyric acid increases transepithelial transport of ferulic acid through upregulation of the monocarboxylate transporters SLC16A1 (MCT1) and SLC16A3 (MCT4).

PubMed

Ziegler, Kerstin; Kerimi, Asimina; Poquet, Laure; Williamson, Gary

2016-06-01

Ferulic acid is released by microbial hydrolysis in the colon, where butyric acid, a major by-product of fermentation, constitutes the main energy source for colonic enterocytes. We investigated how varying concentrations of this short chain fatty acid may influence the absorption of the phenolic acid. Chronic treatment of Caco-2 cells with butyric acid resulted in increased mRNA and protein abundance of the monocarboxylate transporters SLC16A1 (MCT1) and SLC16A3 (MCT4), previously proposed to facilitate ferulic acid absorption in addition to passive diffusion. Short term incubation with butyric acid only led to upregulation of MCT4 while both conditions increased transepithelial transport of ferulic acid in the apical to basolateral, but not basolateral to apical, direction. Chronic treatment also elevated intracellular concentrations of ferulic acid, which in turn gave rise to increased concentrations of ferulic acid metabolites. Immunofluorescence staining of cells revealed uniform distribution of MCT1 protein in the cell membrane, whereas MCT4 was only detected in the lateral plasma membrane sections of Caco-2 cells. We therefore propose that MCT1 may be acting as an uptake transporter and MCT4 as an efflux system across the basolateral membrane for ferulic acid, and that this process is stimulated by butyric acid. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Molecular transport machinery involved in orchestrating luminal acid-induced duodenal bicarbonate secretion in vivo

PubMed Central

Singh, Anurag Kumar; Liu, Yongjian; Riederer, Brigitte; Engelhardt, Regina; Thakur, Basant Kumar; Soleimani, Manoocher; Seidler, Ursula

2013-01-01

The duodenal villus brush border membrane expresses several ion transporters and/or channels, including the solute carrier 26 anion transporters Slc26a3 (DRA) and Slc26a6 (PAT-1), the Na+/H+ exchanger isoform 3 (NHE3), as well as the anion channels cystic fibrosis transmembrane conductance regulator (CFTR) and Slc26a9. Using genetically engineered mouse models lacking Scl26a3, Slc26a6, Slc26a9 or Slc9a3 (NHE3), the study was carried out to assess the role of these transporters in mediating the protective duodenal bicarbonate secretory response (DBS-R) to luminal acid; and to compare it to their role in DBS-R elicited by the adenylyl cyclase agonist forskolin. While basal DBS was reduced in the absence of any of the three Slc26 isoforms, the DBS-R to forskolin was not altered. In contrast, the DBS-R to a 5 min exposure to luminal acid (pH 2.5) was strongly reduced in the absence of Slc26a3 or Slc26a9, but not Slc26a6. CFTR inhibitor [CFTR(Inh)-172] reduced the first phase of the acid-induced DBS-R, while NHE3 inhibition (or knockout) abolished the sustained phase of the DBS-R. Luminal acid exposure resulted in the activation of multiple intracellular signalling pathways, including SPAK, AKT and p38 phosphorylation. It induced a biphasic trafficking of NHE3, first rapidly into the brush border membrane, followed by endocytosis in the later stage. We conclude that the long-lasting DBS-R to luminal acid exposure activates multiple duodenocyte signalling pathways and involves changes in trafficking and/or activity of CFTR, Slc26 isoforms Slc26a3 and Slc26a9, and NHE3. PMID:24018950

Knockdown of SLC39A7 inhibits cell growth and induces apoptosis in human colorectal cancer cells.

PubMed

Sheng, Nengquan; Yan, Li; You, Weiqiang; Tan, Gewen; Gong, Jianfeng; Chen, Hongqi; Yang, Yi; Hu, Landian; Wang, Zhigang

2017-10-01

SLC39A7 (zip7) is a zinc transporter that plays a key role in intestinal epithelial self-renewal. However, little is known about SLC39A7 in colorectal cancer. To assess the biological function of SLC39A7 in colorectal cancer, the expression of SLC39A7 in human colorectal tumors and five colorectal cancer cell lines were evaluated by Oncomine Cancer Microarray Database and western blot analysis. In addition, short hairpin RNAs specifically targeting SLC39A7 were transfected into HCT116 and SW1116 cells to knockdown SLC39A7 expression. Then, the effects of SLC39A7 knockdown on colorectal cancer cells were detected by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide, colony-forming assay and flow cytometry. Our results showed that colorectal tumors have higher expression levels of SLC39A7 than normal colon tissues. Knockdown of SLC39A7 exhibited a significant decrease in cell viability and proliferation of colorectal cancer cells. It was also shown that knockdown of SLC39A7 interfered with cell cycle progression and induced G2/M cell cycle arrest, as well as boosted early and late apoptosis in colorectal cancer cells. Furthermore, downregulation of SLC39A7 promoted the cleavage of PARP and enhanced the expression of Bad, Caspase-9, and cleaved-Caspase-3, as well as suppressed Bcl-2 expression. In conclusion, our results suggest that SLC39A7 plays a crucial role in the proliferation and survival of colorectal cancer cells, which associates with colorectal tumorigenesis. © The Author 2017. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Overexpression of SLC34A2 is an independent prognostic indicator in bladder cancer and its depletion suppresses tumor growth via decreasing c-Myc expression and transcriptional activity

PubMed Central

Ye, Wen; Chen, Cui; Gao, Ying; Zheng, Zou-Shan; Xu, Yi; Yun, Miao; Weng, Hui-Wen; Xie, Dan; Ye, Sheng; Zhang, Jia-Xing

2017-01-01

Solute carrier family 34 member 2 (SLC34A2), a pH-sensitive sodium-dependent phosphate transporter, is associated with several human cancers. In this study, we investigate the clinical significance of SLC34A2 and its function in human bladder cancer (BC). The expression dynamics of SLC34A2 were examined in two independent cohorts of BC samples by quantitative PCR, western blotting and immunohistochemical staining. In the training cohort (156 cases), we applied the X-tile program software to assess the optimal cutoff points for biomarkers in order to accurately classify patients according to clinical outcome. In the validation cohort (130 cases), the cutoff score derived from X-title analysis was investigated to determine the association of SLC34A2 expression with survival outcome. A series of in vitro and in vivo assays were then performed to elucidate the function of SLC34A2 in BC and its underlying mechanisms. Results showed that SLC34A2 was significantly upregulated in BC cell lines and clinical samples. In both two cohorts of BC samples, high expression of SLC34A2 was associated with large tumor size, advanced T status and poor patients' survival. The depletion of SLC34A2 in BC suppressed cellular viability, colony formation and anchorage-independent growth in vitro, and inhibited xenograft tumor growth in vivo, whereas overexpression of SLC34A2 had the converse effect. Simultaneously, downregulation of SLC34A2 decreased the transcriptional activity and protein expression level of c-Myc in BC cells, whereas restoration of c-Myc expression could compromise the anti-proliferation effect of SLC34A2 depletion. Furthermore, miR-214 was proved as a negative regulator of SLC34A2. Our present study illustrated that SLC34A2 has an important role in promoting proliferation and tumorigenicity of BC, and may represent a novel therapeutic target for this disease. PMID:28151475

SLC12A7 alters adrenocortical carcinoma cell adhesion properties to promote an aggressive invasive behavior.

PubMed

Brown, Taylor C; Murtha, Timothy D; Rubinstein, Jill C; Korah, Reju; Carling, Tobias

2018-06-08

Altered expression of Solute Carrier Family 12 Member 7 (SLC12A7) is implicated to promote malignant behavior in multiple cancer types through an incompletely understood mechanism. Recent studies have shown recurrent gene amplifications and overexpression of SLC12A7 in adrenocortical carcinoma (ACC). The potential mechanistic effect(s) of SLC12A7 amplifications in portending an aggressive behavior in ACC has not been previously studied and is investigated here using two established ACC cell lines, SW-13 and NCI-H295R. SW-13 cells, which express negligible amounts of SLC12A7, were enforced to express SLC12A7 constitutively, while RNAi gene silencing was performed in NCI-H295R cells, which have robust endogenous expression of SLC12A7. In vitro studies tested the outcomes of experimental alterations in SLC12A7 expression on malignant characteristics, including cell viability, growth, colony formation potential, motility, invasive capacity, adhesion and detachment kinetics, and cell membrane organization. Further, potential alterations in transcription regulation downstream to induced SLC12A7 overexpression was explored using targeted transcription factor expression arrays. Enforced SLC12A7 overexpression in SW-13 cells robustly promoted motility and invasive characteristics (p < 0.05) without significantly altering cell viability, growth, or colony formation potential. SLC12A7 overexpression also significantly increased rates of cellular attachment and detachment turnover (p < 0.05), potentially propelled by increased filopodia formation and/or Ezrin interaction. In contrast, RNAi gene silencing of SLC12A7 stymied cell attachment strength as well as migration and invasion capacity in NCI-H295R cells. Transcription factor expression analysis identified multiple signally pathways potentially affected by SLC12A7 overexpression, including osmotic stress, bone morphogenetic protein, and Hippo signaling pathways. Amplification of SLC12A7 observed in ACCs is shown here, in vitro, to exacerbate the malignant behavior of ACC cells by promoting invasive capacities, possibly mediated by alterations in multiple signaling pathways, including the osmotic stress pathway.

Mutations in L-type amino acid transporter-2 support SLC7A8 as a novel gene involved in age-related hearing loss

PubMed Central

Murillo-Cuesta, Silvia; Errasti- Murugarren, Ekaitz; Celaya, Adelaida M; Girotto, Giorgia; Vuckovic, Dragana; Mezzavilla, Massimo; Vilches, Clara; Bodoy, Susanna; Sahún, Ignasi; González, Laura; Prat, Esther; Zorzano, Antonio; Dierssen, Mara

2018-01-01

Age-related hearing loss (ARHL) is the most common sensory deficit in the elderly. The disease has a multifactorial etiology with both environmental and genetic factors involved being largely unknown. SLC7A8/SLC3A2 heterodimer is a neutral amino acid exchanger. Here, we demonstrated that SLC7A8 is expressed in the mouse inner ear and that its ablation resulted in ARHL, due to the damage of different cochlear structures. These findings make SLC7A8 transporter a strong candidate for ARHL in humans. Thus, a screening of a cohort of ARHL patients and controls was carried out revealing several variants in SLC7A8, whose role was further investigated by in vitro functional studies. Significant decreases in SLC7A8 transport activity was detected for patient’s variants (p.Val302Ile, p.Arg418His, p.Thr402Met and p.Val460Glu) further supporting a causative role for SLC7A8 in ARHL. Moreover, our preliminary data suggest that a relevant proportion of ARHL cases could be explained by SLC7A8 mutations. PMID:29355479

Slc10A4 - what do we know about the function of this "secret ligand carrier" protein?

PubMed

Borges, Karin

2013-10-01

This commentary discusses the possible functions of a relatively newly described solute carrier protein, Slc10a4, in regards to a recent article by Zelano et al. (2013) published in the January issue of Experimental Neurology, 239, 73-81. Slc10a4 belongs to the sodium-bile acid cotransporter family (Slc10), but does not show plasma membrane transport activity of bile acids and related molecules. It is co-localized with synaptic vesicle transporters for acetylcholine and dopamine. In Slc10a4 lacking mice, Zelano et al. found increased excitability in hippocampal slices and in vivo responses to pilocarpine, but not kainate. These findings are critically examined here. This author speculates on the possible function of Slc10a4, but remains partial about "specific effects of Slc10a4 in cholinergic systems". It is hoped that approaches targeting human SLC10A4 can be discovered for potential clinical use in neurological disorders, such as Alzheimer's and Parkinson's disease, schizophrenia and addiction. Conversely, some side effects are expected due to peripheral Slc10a4 localization in sympathetic and parasympathetic nerves, as well as mast cells. © 2013.

Vandenberg Air Force Base Emission Survey.

DTIC Science & Technology

1983-01-01

1,020 gals) b. SLC-3 Hydrazine Scrubber c. SLC-4 1) West Pad - Two Aerozine-50 Tanks (11,000 gals each) (one emission point) - Unsymmetrical Dimethyl...Launch Complex (SLC)-2 1) Aerozine-50 Tank (880 gal) 2) Nitrogen Tetroxide Tank (1,020 gal) b. SLC-3 Hydrazine Scrubber c. SLC-4 1) West Pad - Two...vapors are put through a scrubber to reduce the amount of fuel vapor entering the atmosphere. Likewise, specific Oxidizer vapors are disposed of by a

Polarization observables using positron beams

NASA Astrophysics Data System (ADS)

Schmidt, Axel

2018-05-01

The discrepancy between polarized and unpolarized measurements of the proton's electromagnetic form factors is striking, and suggests that two-photon exchange (TPE) may be playing a larger role in elastic electron-proton scattering than is estimated in standard radiative corrections formulae. While TPE is difficult to calculate in a model-independent way, it can be determined experimentally from asymmetries between electron-proton and positron-proton scattering. The possibility of a polarized positron beam at Jefferson Lab would open the door to measurements of TPE using polarization observables. In these proceedings, I examine the feasibility of measuring three such observables with positron scattering. Polarization-transfer, specifically the ɛ-dependence for fixed Q2, is an excellent test of TPE, and the ability to compare electrons and positrons would lead to a drastic reduction of systematics. However, such a measurement would be severely statistically limited. Normal single-spin asymmetries (SSAs) probe the imaginary part of the TPE amplitude and can be improved by simultaneous measurements with electron and positron beams. Beam-normal SSAs are too small to be measured with the proposed polarized positron beam, but target-normal SSAs could be feasibly measured with unpolarized positrons in the spectrometer halls. This technique should be included in the physics case for developing a positron source for Jefferson Lab.

High-temperature studies of grain boundaries in ultrafine grained alloys by means of positron lifetime

NASA Astrophysics Data System (ADS)

Würschum, R.; Shapiro, E.; Dittmar, R.; Schaefer, H.-E.

2000-11-01

Atomic free volumes and vacancies in the ultrafine grained alloys Pd84Zr16, Cu 0.1 wt % ZrO2, and Fe91Zr9 were studied by means of positron lifetime. The thermally stable microstructures serve as a novel type of model system for studying positron trapping and annihilation as well as the thermal behavior of vacancy-sized free volumes over a wide temperature range up to ca. 1200 K by making use of a metallic 58Co positron source. In ultrafine grained Cu the thermal formation of lattice vacancies could be observed. In Pd84Zr16 an increase of the specific positron trapping rate of nanovoids and, in addition, detrapping of positrons from free volumes with a mean size slightly smaller than one missing atom in the grain boundaries contributes to a reversible increase of the positron lifetime of more than 60 ps with measuring temperature. In Fe91Zr9 similar linear high-temperature increases of the positron lifetime are observed in the nanocrystalline and the amorphous state. The question of thermal vacancy formation in grain boundaries is addressed taking into account the different types of interface structures of the present alloys.

The multi-scattering model for calculations of positron spatial distribution in the multilayer stacks, useful for conventional positron measurements

NASA Astrophysics Data System (ADS)

Dryzek, Jerzy; Siemek, Krzysztof

2013-08-01

The spatial distribution of positrons emitted from radioactive isotopes into stacks or layered samples is a subject of the presented report. It was found that Monte Carlo (MC) simulations using GEANT4 code are not able to describe correctly the experimental data of the positron fractions in stacks. The mathematical model was proposed for calculations of the implantation profile or positron fractions in separated layers or foils being components of a stack. The model takes into account only two processes, i.e., the positron absorption and backscattering at interfaces. The mathematical formulas were applied in the computer program called LYS-1 (layers profile analysis). The theoretical predictions of the model were in the good agreement with the results of the MC simulations for the semi infinite sample. The experimental verifications of the model were performed on the symmetrical and non-symmetrical stacks of different foils. The good agreement between the experimental and calculated fractions of positrons in components of a stack was achieved. Also the experimental implantation profile obtained using the depth scanning of positron implantation technique is very well described by the theoretical profile obtained within the proposed model. The LYS-1 program allows us also to calculate the fraction of positrons which annihilate in the source, which can be useful in the positron spectroscopy.

PET/CT alignment calibration with a non-radioactive phantom and the intrinsic 176Lu radiation of PET detector

NASA Astrophysics Data System (ADS)

Wei, Qingyang; Ma, Tianyu; Wang, Shi; Liu, Yaqiang; Gu, Yu; Dai, Tiantian

2016-11-01

Positron emission tomography/computed tomography (PET/CT) is an important tool for clinical studies and pre-clinical researches which provides both functional and anatomical images. To achieve high quality co-registered PET/CT images, alignment calibration of PET and CT scanner is a critical procedure. The existing methods reported use positron source phantoms imaged both by PET and CT scanner and then derive the transformation matrix from the reconstructed images of the two modalities. In this paper, a novel PET/CT alignment calibration method with a non-radioactive phantom and the intrinsic 176Lu radiation of the PET detector was developed. Firstly, a multi-tungsten-alloy-sphere phantom without positron source was designed and imaged by CT and the PET scanner using intrinsic 176Lu radiation included in LYSO. Secondly, the centroids of the spheres were derived and matched by an automatic program. Lastly, the rotation matrix and the translation vector were calculated by least-square fitting of the centroid data. The proposed method was employed in an animal PET/CT system (InliView-3000) developed in our lab. Experimental results showed that the proposed method achieves high accuracy and is feasible to replace the conventional positron source based methods.

Soy-dairy protein blend and whey protein ingestion after resistance exercise increases amino acid transport and transporter expression in human skeletal muscle.

PubMed

Reidy, P T; Walker, D K; Dickinson, J M; Gundermann, D M; Drummond, M J; Timmerman, K L; Cope, M B; Mukherjea, R; Jennings, K; Volpi, E; Rasmussen, B B

2014-06-01

Increasing amino acid availability (via infusion or ingestion) at rest or postexercise enhances amino acid transport into human skeletal muscle. It is unknown whether alterations in amino acid availability, from ingesting different dietary proteins, can enhance amino acid transport rates and amino acid transporter (AAT) mRNA expression. We hypothesized that the prolonged hyperaminoacidemia from ingesting a blend of proteins with different digestion rates postexercise would enhance amino acid transport into muscle and AAT expression compared with the ingestion of a rapidly digested protein. In a double-blind, randomized clinical trial, we studied 16 young adults at rest and after acute resistance exercise coupled with postexercise (1 h) ingestion of either a (soy-dairy) protein blend or whey protein. Phenylalanine net balance and transport rate into skeletal muscle were measured using stable isotopic methods in combination with femoral arteriovenous blood sampling and muscle biopsies obtained at rest and 3 and 5 h postexercise. Phenylalanine transport into muscle and mRNA expression of select AATs [system L amino acid transporter 1/solute-linked carrier (SLC) 7A5, CD98/SLC3A2, system A amino acid transporter 2/SLC38A2, proton-assisted amino acid transporter 1/SLC36A1, cationic amino acid transporter 1/SLC7A1] increased to a similar extent in both groups (P < 0.05). However, the ingestion of the protein blend resulted in a prolonged and positive net phenylalanine balance during postexercise recovery compared with whey protein (P < 0.05). Postexercise myofibrillar protein synthesis increased similarly between groups. We conclude that, while both protein sources enhanced postexercise AAT expression, transport into muscle, and myofibrillar protein synthesis, postexercise ingestion of a protein blend results in a slightly prolonged net amino acid balance across the leg compared with whey protein. Copyright © 2014 the American Physiological Society.

Soy-dairy protein blend and whey protein ingestion after resistance exercise increases amino acid transport and transporter expression in human skeletal muscle

PubMed Central

Reidy, P. T.; Walker, D. K.; Dickinson, J. M.; Gundermann, D. M.; Drummond, M. J.; Timmerman, K. L.; Cope, M. B.; Mukherjea, R.; Jennings, K.; Volpi, E.

2014-01-01

Increasing amino acid availability (via infusion or ingestion) at rest or postexercise enhances amino acid transport into human skeletal muscle. It is unknown whether alterations in amino acid availability, from ingesting different dietary proteins, can enhance amino acid transport rates and amino acid transporter (AAT) mRNA expression. We hypothesized that the prolonged hyperaminoacidemia from ingesting a blend of proteins with different digestion rates postexercise would enhance amino acid transport into muscle and AAT expression compared with the ingestion of a rapidly digested protein. In a double-blind, randomized clinical trial, we studied 16 young adults at rest and after acute resistance exercise coupled with postexercise (1 h) ingestion of either a (soy-dairy) protein blend or whey protein. Phenylalanine net balance and transport rate into skeletal muscle were measured using stable isotopic methods in combination with femoral arteriovenous blood sampling and muscle biopsies obtained at rest and 3 and 5 h postexercise. Phenylalanine transport into muscle and mRNA expression of select AATs [system L amino acid transporter 1/solute-linked carrier (SLC) 7A5, CD98/SLC3A2, system A amino acid transporter 2/SLC38A2, proton-assisted amino acid transporter 1/SLC36A1, cationic amino acid transporter 1/SLC7A1] increased to a similar extent in both groups (P < 0.05). However, the ingestion of the protein blend resulted in a prolonged and positive net phenylalanine balance during postexercise recovery compared with whey protein (P < 0.05). Postexercise myofibrillar protein synthesis increased similarly between groups. We conclude that, while both protein sources enhanced postexercise AAT expression, transport into muscle, and myofibrillar protein synthesis, postexercise ingestion of a protein blend results in a slightly prolonged net amino acid balance across the leg compared with whey protein. PMID:24699854

Developmental expression of SLC26A4 (Pendrin) during amelogenesis in developing rodent teeth

PubMed Central

Bronckers, Antonius LJJ; Guo, Jing; Zandieh-Doulabi, Behrouz; Bervoets, Theodore J; Lyaruu, Donacian M.; Li, Xiangming; Wangemann, Philine; DenBesten, Pamela

2012-01-01

Ameloblasts need to regulate pH during formation of enamel crystals, a process that generates protons. Solute carrier family 26A member 4 (SLC26A4, or pendrin) is an anion exchanger for chloride, bicarbonate, iodine and formate. It is expressed in apical membranes of ion-transporting epithelia in kidney, inner ear and thyroid where it regulates luminal pH and fluid transport. We hypothesized that maturation ameloblasts express SLC26A4 to neutralize acidification of enamel fluid in forming enamel. In rodents, secretory and maturation ameloblasts were immunopositive for SLC26A4. Staining was particularly strong in apical membranes of maturation ameloblasts facing forming enamel. RT-PCR confirmed the presence of mRNA transcripts for Slc26a4 in enamel organs. SLC26A4 immunostaining was also found in mineralizing connective tissues including odontoblasts, osteoblasts, osteocytes, osteoclasts, bone lining cells, cellular cementoblasts and cementocytes. However, Slc26a4-null mutant mice had no overt dental phenotype. The presence of SLC26A4 in apical plasma membranes of maturation ameloblasts is consistent with a potential function as pH regulator. SLC26A4 does not appear critical for ameloblast functioning and is likely compensated by other pH regulators. PMID:22243245

Riboflavin uptake transporter Slc52a2 (RFVT2) is upregulated in the mouse mammary gland during lactation.

PubMed

Wu, Alex Man Lai; Dedina, Liana; Dalvi, Pooja; Yang, Mingdong; Leon-Cheon, John; Earl, Brian; Harper, Patricia A; Ito, Shinya

2016-04-01

While it is well recognized that riboflavin accumulates in breast milk as an essential vitamin for neonates, transport mechanisms for its milk excretion are not well characterized. The multidrug efflux transporter ABCG2 in the apical membrane of milk-producing mammary epithelial cells (MECs) is involved with riboflavin excretion. However, it is not clear whether MECs possess other riboflavin transport systems, which may facilitate its basolateral uptake into MECs. We report here that transcripts encoding the second (SLC52A2) and third (SLC52A3) member of the recently discovered family of SLC52A riboflavin uptake transporters are expressed in milk fat globules from human breast milk. Furthermore, Slc52a2 and Slc52a3 mRNA are upregulated in the mouse mammary gland during lactation. Importantly, the induction ofSlc52a2, which was the major Slc52a riboflavin transporter in the lactating mammary gland, was also observed at the protein level. Subcellular localization studies showed that green fluorescent protein-tagged mouse SLC52A2 mainly localized to the cell membrane, with no preferential distribution to the apical or basolateral membrane in polarized kidney MDCK cells. These results strongly implicate a potential role for SLC52A2 in riboflavin uptake by milk-producing MECs, a critical step in the transfer of riboflavin into breast milk. Copyright © 2016 the American Physiological Society.

Expression of ion transport-associated proteins in human efferent and epididymal ducts.

PubMed

Kujala, Minna; Hihnala, Satu; Tienari, Jukka; Kaunisto, Kari; Hästbacka, Johanna; Holmberg, Christer; Kere, Juha; Höglund, Pia

2007-04-01

Appropriate intraluminal microenvironment in the epididymis is essential for maturation of sperm. To clarify whether the anion transporters SLC26A2, SLC26A6, SLC26A7, and SLC26A8 might participate in generating this proper intraluminal milieu, we studied the localization of these proteins in the human efferent and the epididymal ducts by immunohistochemistry. In addition, immunohistochemistry of several SLC26-interacting proteins was performed: the Na(+)/H(+) exchanger 3 (NHE3), the Cl(-) channel cystic fibrosis transmembrane conductance regulator (CFTR), the proton pump V-ATPase, their regulator Na(+)/H(+) exchanger regulating factor 1 (NHERF-1), and carbonic anhydrase II (CAII). Our results show that SLC26A6, CFTR, NHE3, and NHERF-1 are co-expressed on the apical side of the nonciliated cells, and SLC26A2 appears in the cilia of the ciliated cells in the human efferent ducts. In the epididymal ducts, SLC26A6, CFTR, NHERF-1, CAII, and V-ATPase (B and E subunits) were co-localized to the apical mitochondria rich cells, while SLC26A7 was expressed in a subgroup of basal cells. SLC26A8 was not found in the structures studied. This is the first study describing the localization of SLC26A2, A6 and A7, and NHERF-1 in the efferent and the epididymal ducts. Immunolocalization of human CFTR, NHE3, CAII, and V-ATPase in these structures differs partly from previous reports from rodents. Our findings suggest roles for these proteins in male fertility, either independently or through interaction and reciprocal regulation with co-localized proteins shown to affect fertility, when disrupted.

Increased cortical expression of the zinc transporter SLC39A12 suggests a breakdown in zinc cellular homeostasis as part of the pathophysiology of schizophrenia

PubMed Central

Scarr, Elizabeth; Udawela, Madhara; Greenough, Mark A; Neo, Jaclyn; Suk Seo, Myoung; Money, Tammie T; Upadhyay, Aradhana; Bush, Ashley I; Everall, Ian P; Thomas, Elizabeth A; Dean, Brian

2016-01-01

Our expression microarray studies showed messenger RNA (mRNA) for solute carrier family 39 (zinc transporter), member 12 (SLC39A12) was higher in dorsolateral prefrontal cortex from subjects with schizophrenia (Sz) in comparison with controls. To better understand the significance of these data we ascertained whether SLC39A12 mRNA was altered in a number of cortical regions (Brodmann’s area (BA) 8, 9, 44) from subjects with Sz, in BA 9 from subjects with mood disorders and in rats treated with antipsychotic drugs. In addition, we determined whether inducing the expression of SLC39A12 resulted in an increased cellular zinc uptake. SLC39A12 variant 1 and 2 mRNA was measured using quantitative PCR. Zinc uptake was measured in CHO cells transfected with human SLC39A12 variant 1 and 2. In Sz, compared with controls, SLC39A12 variant 1 and 2 mRNA was higher in all cortical regions studied. The were no differences in levels of mRNA for either variant of SLC39A12 in BA 9 from subjects with mood disorders and levels of mRNA for Slc39a12 was not different in the cortex of rats treated with antipsychotic drugs. Finally, expressing both variants in CHO-K1 cells was associated with an increase in radioactive zinc uptake. As increased levels of murine Slc39a12 mRNA has been shown to correlate with increasing cellular zinc uptake, our data would be consistent with the possibility of a dysregulated zinc homeostasis in the cortex of subjects with schizophrenia due to altered expression of SLC39A12. PMID:27336053

Expression of solute carrier 7A4 (SLC7A4) in the plasma membrane is not sufficient to mediate amino acid transport activity.

PubMed

Wolf, Sabine; Janzen, Annette; Vékony, Nicole; Martiné, Ursula; Strand, Dennis; Closs, Ellen I

2002-06-15

Member 4 of human solute carrier family 7 (SLC7A4) exhibits significant sequence homology with the SLC7 subfamily of human cationic amino acid transporters (hCATs) [Sperandeo, Borsani, Incerti, Zollo, Rossi, Zuffardi, Castaldo, Taglialatela, Andria and Sebastio (1998) Genomics 49, 230-236]. It is therefore often referred to as hCAT-4 even though no convincing transport activity has been shown for this protein. We expressed SLC7A4 in Xenopus laevis oocytes, but could not detect any transport activity for cationic, neutral or anionic amino acids or for the polyamine putrescine. In addition, human glioblastoma cells stably overexpressing a fusion protein between SLC7A4 and the enhanced green fluorescent protein (EGFP) did not exhibit an increased transport activity for l-arginine. The lack of transport activity was not due to a lack of SLC7A4 protein expression in the plasma membrane, as in both cell types SLC7A4-EGFP exhibited a similar subcellular localization and level of protein expression as functional hCAT-EGFP proteins. The expression of SLC7A4 can be induced in NT2 teratocarcinoma cells by treatment with retinoic acid. However, also for this endogenously expressed SLC7A4, we could not detect any transport activity for l-arginine. Our data demonstrate that the expression of SLC7A4 in the plasma membrane is not sufficient to induce an amino acid transport activity in X. laevis oocytes or human cells. Therefore, SLC7A4 is either not an amino acid transporter or it needs additional (protein) factor(s) to be functional.

Expression of solute carrier 7A4 (SLC7A4) in the plasma membrane is not sufficient to mediate amino acid transport activity.

PubMed Central

Wolf, Sabine; Janzen, Annette; Vékony, Nicole; Martiné, Ursula; Strand, Dennis; Closs, Ellen I

2002-01-01

Member 4 of human solute carrier family 7 (SLC7A4) exhibits significant sequence homology with the SLC7 subfamily of human cationic amino acid transporters (hCATs) [Sperandeo, Borsani, Incerti, Zollo, Rossi, Zuffardi, Castaldo, Taglialatela, Andria and Sebastio (1998) Genomics 49, 230-236]. It is therefore often referred to as hCAT-4 even though no convincing transport activity has been shown for this protein. We expressed SLC7A4 in Xenopus laevis oocytes, but could not detect any transport activity for cationic, neutral or anionic amino acids or for the polyamine putrescine. In addition, human glioblastoma cells stably overexpressing a fusion protein between SLC7A4 and the enhanced green fluorescent protein (EGFP) did not exhibit an increased transport activity for l-arginine. The lack of transport activity was not due to a lack of SLC7A4 protein expression in the plasma membrane, as in both cell types SLC7A4-EGFP exhibited a similar subcellular localization and level of protein expression as functional hCAT-EGFP proteins. The expression of SLC7A4 can be induced in NT2 teratocarcinoma cells by treatment with retinoic acid. However, also for this endogenously expressed SLC7A4, we could not detect any transport activity for l-arginine. Our data demonstrate that the expression of SLC7A4 in the plasma membrane is not sufficient to induce an amino acid transport activity in X. laevis oocytes or human cells. Therefore, SLC7A4 is either not an amino acid transporter or it needs additional (protein) factor(s) to be functional. PMID:12049641

Molecular pathophysiology of SLC4 bicarbonate transporters.

PubMed

Romero, Michael F

2005-09-01

Acid-base (H and HCO3) transport in the kidney is crucial for maintaining blood pH, cellular pH and excreting metabolic acid. HCO3 transport in the kidney is mediated by HCO3 transporter proteins which occur in two gene families in humans, vertebrates and invertebrates (SLC4 and SLC26). Since SLC26 transporters have other, non-HCO3 transport functions, this review highlights the history and recent advances in the SLC4 transporters in the kidney. The SLC4 gene and protein family (10 genes) contains three types of HCO3 transporters: Cl-HCO3 exchangers, Na/HCO3 cotransporters and Na-driven Cl-HCO3 exchangers. Function and human chromosomal location have been determined for most members. Human mutations in AE1 (SLC4A1) and NBCe1 (SLC4A4) are associated with distal and proximal renal tubular acidosis, respectively. Recent advances include the cellular and biophysical mechanisms by which AE1 and NBCe1 mutations lead to renal disease. Mutational and cellular trafficking studies have begun to elucidate the membrane topology and functional domains of AE1 and NBCe1. Knockout mice for AE2 and NBCn1 do not have obvious renal phenotypes. Recently, SLC4A11 (bicarbonate transporter 1) was shown to function as an electrogenic Na/borate cotransporter unable to transport HCO3 but involved in cell cycle control. SLC4 HCO3 transporters play critical roles in systemic and cellular pH homeostasis. Most of the SLC4 members are present at some level in the kidney. Future studies will likely continue to make use of knockout animals, for example mice and zebrafish, human mutations or polymorphisms to elucidate the normal and pathophysiologic roles of these proteins.

Association of SLC11A1 with tuberculosis interactions with NOS2A and TLR2 in African-Americans and Caucasians

PubMed Central

Velez, D.R.; Hulme, W.F.; Myers, J.L.; Stryjewski, M.E.; Abbate, E.; Estevan, R.; Patillo, S.G.; Gilbert, J.R.; Hamilton, C.D.; Scott, W.K.

2010-01-01

SETTING Host defense factors may influence the development of active tuberculosis (TB). OBJECTIVE To test variants in solute carrier family 11A, member 1 (SLC11A1), for an association with TB. METHODS A mixed case-control study of TB cases, relatives or close contact controls, consisting of 474 African-Americans (243 families) and 381 Caucasians (192 families), examined 13 SLC11A1 polymorphisms for association with pulmonary TB using generalized estimating equations adjusting for age and gender. RESULTS Two associations were observed in Caucasians (rs3731863, P = 0.03, and rs17221959, P = 0.04) and one in African-Americans (rs3731865, P = 0.05). Multilocus analyses between polymorphisms in SLC11A1 and 11 TB candidate genes detected interactions between SLC11A1 and inducible nitric oxide synthase (NOS2A) in Caucasians (rs3731863 [SLC11A1] × rs8073782 [NOS2A], P = 0.009; rs3731863 [SLC11A1] × rs17722851 [NOS2A], P = 0.007) and toll-like receptor 2 (TLR2) in African-Americans (rs3731865 [SLC11A1] x rs1816702, P = 0.005). CONCLUSIONS No association was detected with 5′(GT)n promoter polymorphism previously associated with lower SLC11A1 expression, rs17235409 (D543N), or rs17235416 (3′ TGTG insertion/deletion polymorphism). SLC11A1 polymorphism rs3731865 was associated with TB in African-Americans, consistent with previous findings in West Africans. These results suggest that variants in SLC11A1 increase susceptibility to pulmonary TB and interact with other variants that differ by race. PMID:19723394

Molecular analysis of the human SLC13A4 sulfate transporter gene promoter

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jefferis, J.; Rakoczy, J.; School of Biomedical Sciences, University of Queensland, St. Lucia, Queensland

2013-03-29

Highlights: ► Basal promoter activity of SLC13A4 −57 to −192 nt upstream of transcription initiation site. ► Human SLC13A4 5′-flanking region has conserved motifs with other placental species. ► Putative NFY, SP1 and KLF7 motifs in SLC13A4 5′-flanking region enhance transcription. -- Abstract: The human solute linked carrier (SLC) 13A4 gene is primarily expressed in the placenta where it is proposed to mediate the transport of nutrient sulfate from mother to fetus. The molecular mechanisms involved in the regulation of SLC13A4 expression remain unknown. To investigate the regulation of SLC13A4 gene expression, we analysed the transcriptional activity of the humanmore » SLC13A4 5′-flanking region in the JEG-3 placental cell line using luciferase reporter assays. Basal transcriptional activity was identified in the region −57 to −192 nucleotides upstream of the SLC13A4 transcription initiation site. Mutational analysis of the minimal promoter region identified Nuclear factor Y (NFY), Specificity protein 1 (SP1) and Krüppel like factor 7 (KLF7) motifs which conferred positive transcriptional activity, as well as Zinc finger protein of the cerebellum 2 (ZIC2) and helix–loop–helix protein 1 (HEN1) motifs that repressed transcription. The conserved NFY, SP1, KLF7, ZIC2 and HEN1 motifs in the SLC13A4 promoter of placental species but not in non-placental species, suggests a potential role for these putative transcriptional factor binding motifs in the physiological control of SLC13A4 mRNA expression.« less

The systems biology of uric acid transporters: the role of remote sensing and signaling.

PubMed

Nigam, Sanjay K; Bhatnagar, Vibha

2018-07-01

Uric acid homeostasis in the body is mediated by a number of SLC and ABC transporters in the kidney and intestine, including several multispecific 'drug' transporters (e.g., OAT1, OAT3, and ABCG2). Optimization of uric acid levels can be viewed as a 'systems biology' problem. Here, we consider uric acid transporters from a systems physiology perspective using the framework of the 'Remote Sensing and Signaling Hypothesis.' This hypothesis explains how SLC and ABC 'drug' and other transporters mediate interorgan and interorganismal communication (e.g., gut microbiome and host) via small molecules (e.g., metabolites, antioxidants signaling molecules) through transporters expressed in tissues lining body fluid compartments (e.g., blood, urine, cerebrospinal fluid). The list of uric acid transporters includes: SLC2A9, ABCG2, URAT1 (SLC22A12), OAT1 (SLC22A6), OAT3 (SLC22A8), OAT4 (SLC22A11), OAT10 (SLC22A13), NPT1 (SLC17A1), NPT4 (SLC17A3), MRP2 (ABCC2), MRP4 (ABCC4). Normally, SLC2A9, - along with URAT1, OAT1 and OAT3, - appear to be the main transporters regulating renal urate handling, while ABCG2 appears to regulate intestinal transport. In chronic kidney disease (CKD), intestinal ABCG2 becomes much more important, suggesting remote organ communication between the injured kidney and the intestine. The remote sensing and signaling hypothesis provides a useful systems-level framework for understanding the complex interplay of uric acid transporters expressed in different tissues involved in optimizing uric acid levels under normal and diseased (e.g., CKD, gut microflora dysbiosis) conditions.

Polymorphic Imprinting of SLC38A4 Gene in Bovine Placenta.

PubMed

Xu, Da; Zhang, Cui; Li, Junliang; Wang, Guannan; Chen, Weina; Li, Dongjie; Li, Shijie

2018-05-21

Imprinted genes are characterized by monoallelic expression that is dependent on parental origin. Comparative analysis of imprinted genes between species is a powerful tool for understanding the biological significance of genomic imprinting. The slc38a4 gene encodes a neutral amino acid transporter and is identified as imprinted in mice. In this study, the imprinting status of SLC38A4 was assessed in bovine adult tissues and placenta using a polymorphism-based approach. Results indicate that SLC38A4 is not imprinted in eight adult bovine tissues including heart, liver, spleen, lung, kidney, muscle, fat, and brain. It was interesting to note that SLC38A4 showed polymorphic status in five heterogeneous placentas, with three exhibiting paternal monoallelic expression and two exhibiting biallelic expression. Monoallelic expression of imprinted genes is generally associated with allele-specific differentially methylation regions (DMRs) of CpG islands (CGIs)-encompassed promoter; therefore, the DNA methylation statuses of three CGIs in the SLC38A4 promoter and exon 1 region were tested in three placentas (two exhibiting paternal monoallelic and one showing biallelic expression of SLC38A4) and their corresponding paternal sperms. Unexpectedly, extreme hypomethylation (< 3%) of the DNA was observed in all the three detected placentas and their corresponding paternal sperms. The absence of DMR in bovine SLC38A4 promoter region implied that DNA methylation of these three CGIs does not directly or indirectly affect the polymorphic imprinting of SLC38A4 in bovine placenta. This suggested other epigenetic features other than DNA methylation are needed in regulating the imprinting of bovine SLC38A4, which is different from that of mouse with respect to a DMR existence at the mouse's slc38a4 promoter region. Although further work is needed, this first characterization of polymorphic imprinting status of SLC38A4 in cattle placenta provides valuable information on investigating the genomic imprinting phenomenon itself.

Critical Roles of Two Hydrophobic Residues within Human Glucose Transporter 9 (hSLC2A9) in Substrate Selectivity and Urate Transport*

PubMed Central

Long, Wentong; Panwar, Pankaj; Witkowska, Kate; Wong, Kenneth; O'Neill, Debbie; Chen, Xing-Zhen; Lemieux, M. Joanne; Cheeseman, Chris I.

2015-01-01

High blood urate levels (hyperuricemia) have been found to be a significant risk factor for cardiovascular diseases and inflammatory arthritis, such as hypertension and gout. Human glucose transporter 9 (hSLC2A9) is an essential protein that mainly regulates urate/hexose homeostasis in human kidney and liver. hSLC2A9 is a high affinity-low capacity hexose transporter and a high capacity urate transporter. Our previous studies identified a single hydrophobic residue in trans-membrane domain 7 of class II glucose transporters as a determinant of fructose transport. A mutation of isoleucine 335 to valine (I355V) in hSLC2A9 can reduce fructose transport while not affecting glucose fluxes. This current study demonstrates that the I335V mutant transports urate similarly to the wild type hSLC2A9; however, Ile-335 is necessary for urate/fructose trans-acceleration exchange to occur. Furthermore, Trp-110 is a critical site for urate transport. Two structural models of the class II glucose transporters, hSLC2A9 and hSLC2A5, based on the crystal structure of hSLC2A1 (GLUT1), reveal that Ile-335 (or the homologous Ile-296 in hSLC2A5) is a key component for protein conformational changes when the protein translocates substrates. The hSLC2A9 model also predicted that Trp-110 is a crucial site that could directly interact with urate during transport. Together, these studies confirm that hSLC2A9 transports both urate and fructose, but it interacts with them in different ways. Therefore, this study advances our understanding of how hSLC2A9 mediates urate and fructose transport, providing further information for developing pharmacological agents to treat hyperuricemia and related diseases, such as gout, hypertension, and diabetes. PMID:25922070

SLC26 anion exchangers of guinea pig pancreatic duct: molecular cloning and functional characterization

PubMed Central

Stewart, Andrew K.; Shmukler, Boris E.; Vandorpe, David H.; Reimold, Fabian; Heneghan, John F.; Nakakuki, M.; Akhavein, Arash; Ko, Shigeru; Ishiguro, Hiroshi

2011-01-01

The secretin-stimulated human pancreatic duct secretes HCO3−-rich fluid essential for normal digestion. Optimal stimulation of pancreatic HCO3− secretion likely requires coupled activities of the cystic fibrosis transmembrane regulator (CFTR) anion channel and apical SLC26 Cl−/HCO3− exchangers. However, whereas stimulated human and guinea pig pancreatic ducts secrete ∼140 mM HCO3− or more, mouse and rat ducts secrete ∼40–70 mM HCO3−. Moreover, the axial distribution and physiological roles of SLC26 anion exchangers in pancreatic duct secretory processes remain controversial and may vary among mammalian species. Thus the property of high HCO3− secretion shared by human and guinea pig pancreatic ducts prompted us to clone from guinea pig pancreatic duct cDNAs encoding Slc26a3, Slc26a6, and Slc26a11 polypeptides. We then functionally characterized these anion transporters in Xenopus oocytes and human embryonic kidney (HEK) 293 cells. In Xenopus oocytes, gpSlc26a3 mediated only Cl−/Cl− exchange and electroneutral Cl−/HCO3− exchange. gpSlc26a6 in Xenopus oocytes mediated Cl−/Cl− exchange and bidirectional exchange of Cl− for oxalate and sulfate, but Cl−/HCO3− exchange was detected only in HEK 293 cells. gpSlc26a11 in Xenopus oocytes exhibited pH-dependent Cl−, oxalate, and sulfate transport but no detectable Cl−/HCO3− exchange. The three gpSlc26 anion transporters exhibited distinct pharmacological profiles of 36Cl− influx, including partial sensitivity to CFTR inhibitors Inh-172 and GlyH101, but only Slc26a11 was inhibited by PPQ-102. This first molecular and functional assessment of recombinant SLC26 anion transporters from guinea pig pancreatic duct enhances our understanding of pancreatic HCO3− secretion in species that share a high HCO3− secretory output. PMID:21593449

Na+-taurocholate cotransporting polypeptide (NTCP/SLC10A1) ortholog in the marine skate Leucoraja erinacea is not a physiological bile salt transporter

PubMed Central

Yu, Dongke; Zhang, Han; Lionarons, Daniel A.; Boyer, James L.

2017-01-01

The Na+-dependent taurocholate cotransporting polypeptide (NTCP/SLC10A1) is a hepatocyte-specific solute carrier, which plays an important role in maintaining bile salt homeostasis in mammals. The absence of a hepatic Na+-dependent bile salt transport system in marine skate and rainbow trout raises a question regarding the function of the Slc10a1 gene in these species. Here, we have characterized the Slc10a1 gene in the marine skate, Leucoraja erinacea. The transcript of skate Slc10a1 (skSlc10a1) encodes 319 amino acids and shares 46% identity to human NTCP (hNTCP) with similar topology to mammalian NTCP. SkSlc10a1 mRNA was mostly confined to the brain and testes with minimal expression in the liver. An FXR-bile salt reporter assay indicated that skSlc10a1 transported taurocholic acid (TCA) and scymnol sulfate, but not as effectively as hNTCP. An [3H]TCA uptake assay revealed that skSlc10a1 functioned as a Na+-dependent transporter, but with low affinity for TCA (Km = 92.4 µM) and scymnol sulfate (Ki = 31 µM), compared with hNTCP (TCA, Km = 5.4 µM; Scymnol sulfate, Ki = 3.5 µM). In contrast, the bile salt concentration in skate plasma was 2 µM, similar to levels seen in mammals. Interestingly, skSlc10a1 demonstrated transport activity for the neurosteroids dehydroepiandrosterone sulfate and estrone-3-sulfate at physiological concentration, similar to hNTCP. Together, our findings indicate that skSlc10a1 is not a physiological bile salt transporter, providing a molecular explanation for the absence of a hepatic Na+-dependent bile salt uptake system in skate. We speculate that Slc10a1 is a neurosteroid transporter in skate that gained its substrate specificity for bile salts later in vertebrate evolution. PMID:28077388

Increased expression of Solute carrier family 12 member 5 via gene amplification contributes to tumour progression and metastasis and associates with poor survival in colorectal cancer

PubMed Central

Xu, Lixia; Li, Xiaoxing; Cai, Muyan; Chen, Jinna; Li, Xiangchun; Wu, William K K; Kang, Wei; Tong, Joanna; To, Ka-Fai; Guan, Xin-Yuan; Sung, Joseph J Y; Chan, Francis K L; Yu, Jun

2016-01-01

Objective Using whole genome sequencing, we identified gene amplification of solute carrier family 12 member 5 (SLC12A5) located at 20q13.12 in colorectal cancer (CRC). We analysed its amplification, overexpression, biological effects and prognostic significance in CRC. Design SLC12A5 amplification status was evaluated by fluorescence in situ hybridisation (FISH). The effects of SLC12A5 re-expression or knockdown were determined in proliferation, apoptosis, invasion and metastasis assays. SLC12A5 target genes and related pathways were identified by reporter activity and cDNA microarray analyses. Clinical impact of SLC12A5 overexpression was assessed in 195 patients with CRC. Results Amplification of SLC12A5 was verified in 78 out of 191 (40.8%) patients with primary CRC by FISH, which was positively correlated with its protein overexpression (p<0.001). Biofunctional investigation of SLC12A5 revealed that SLC12A5 significantly increased cell proliferation, G1-S cell cycle transition, invasion/migration abilities, but suppressed apoptosis in vitro and promoted xenograft tumour growth as well as lung metastasis in vivo. The antiapoptosis effect by SLC12A5 was mediated through inhibiting apoptosis-inducing factor and endonuclease G-dependent apoptotic signalling pathway; and the pro-metastasis role was by regulating key elements of the matrix architecture, including matrix metallopeptidase and fibronectin. After a median follow-up of 50.16 months, multivariate analysis revealed that patients with SLC12A5 protein overexpression had a significant decrease in overall survival. Kaplan–Meier survival curves showed that SLC12A5 overexpression was significantly associated with shortened survival in patients with CRC. Conclusions SLC12A5 plays a pivotal oncogenic role in colorectal carcinogenesis; its overexpression is an independent prognostic factor of patients with CRC. PMID:25947013

SLC4A11 is an EIPA-sensitive Na+ permeable pHi regulator

PubMed Central

Ogando, Diego G.; Jalimarada, Supriya S.; Zhang, Wenlin; Vithana, Eranga N.

2013-01-01

Slc4a11, a member of the solute linked cotransporter 4 family that is comprised predominantly of bicarbonate transporters, was described as an electrogenic 2Na+-B(OH)4− (borate) cotransporter and a Na+-2OH− cotransporter. The goal of the current study was to confirm and/or clarify the function of SLC4A11. In HEK293 cells transfected with SLC4A11 we tested if SLC4A11 is a: 1) Na+-HCO3− cotransporter, 2) Na+-OH−(H+) transporter, and/or 3) Na+-B(OH)4− cotransporter. CO2/HCO3− perfusion yielded no significant differences in rate or extent of pHi changes or Na+ flux in SLC4A11-transfected compared with control cells. Similarly, in CO2/HCO3−, acidification on removal of Na+ and alkalinization on Na+ add back were not significantly different between control and transfected indicating that SLC4A11 does not have Na+-HCO3− cotransport activity. In the absence of CO2/HCO3−, SLC4A11-transfected cells showed higher resting intracelllular Na+ concentration ([Na+]i; 25 vs. 17 mM), increased NH4+-induced acidification and increased acid recovery rate (160%) after an NH4 pulse. Na+ efflux and influx were faster (80%) following Na+ removal and add back, respectively, indicative of Na+-OH−(H+) transport by SLC4A11. The increased alkalinization recovery was confirmed in NHE-deficient PS120 cells demonstrating that SLC4A11 is a bonafide Na+-OH−(H+) transporter and not an activator of NHEs. SLC4A11-mediated H+ efflux is inhibited by 5-(N-ethyl-N-isopropyl) amiloride (EIPA; EC50: 0.1 μM). The presence of 10 mM borate did not alter dpHi/dt or ΔpH during a Na+-free pulse in SLC4A11-transfected cells. In summary our results show that SLC4A11 is not a bicarbonate or borate-linked transporter but has significant EIPA-sensitive Na+-OH−(H+) and NH4+ permeability. PMID:23864606

Ion Transport Function of SLC4A11 in Corneal Endothelium

PubMed Central

Jalimarada, Supriya S.; Ogando, Diego G.; Vithana, Eranga N.; Bonanno, Joseph A.

2013-01-01

Purpose. Mutations in SLC4A11, a member of the SLC4 superfamily of bicarbonate transporters, give rise to corneal endothelial cell dystrophies. SLC4A11 is a putative Na+ borate and Na+:OH− transporter. Therefore we ask whether SLC4A11 in corneal endothelium transports borate (B[OH]4−), bicarbonate (HCO3−), or hydroxyl (OH−) anions coupled to Na+. Methods. SLC4A11 expression in cultured primary bovine corneal endothelial cells (BCECs) was determined by semiquantitative PCR, SDS-PAGE/Western blotting, and immunofluorescence staining. Ion transport function was examined by measuring intracellular pH (pHi) or Na+ ([Na+]i) in response to Ringer solutions with/without B(OH)4− or HCO3− after overexpressing or small interfering RNA (siRNA) silencing of SLC4A11. Results. SLC4A11 is localized to the basolateral membrane in BCEC. B(OH)4− (2.5–10 mM) in bicarbonate-free Ringer induced a rapid small acidification (0.01 pH unit) followed by alkalinization (0.05–0.1 pH unit), consistent with diffusion of boric acid into the cell followed by B(OH)4−. However, the rate of B(OH)4−-induced pHi change was unaffected by overexpression of SLC4A11. B(OH)4− did not induce significant changes in resting [Na+i] or the amplitude and rate of acidification caused by Na+ removal. siRNA-mediated knockdown of SLC4A11 (∼70%) did not alter pHi responses to CO2/HCO3−-rich Ringer, Na+-free induced acidification, or the rate of Na+ influx in the presence of bicarbonate. However, in the absence of bicarbonate, siSLC4A11 knockdown significantly decreased the rate (43%) and amplitude (48%) of acidification due to Na+ removal and recovery (53%) upon add-back. Additionally, the rate of acid recovery following NH4+ prepulse was decreased significantly (27%) by SLC4A11 silencing. Conclusions. In corneal endothelium, SLC4A11 displays robust Na+-coupled OH− transport, but does not transport B(OH)4− or HCO3−. PMID:23745003

(The AMY experiment)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

1989-01-01

The AMY experiment is one of three major experiments at TRISTAN which is studying the states the matter produced in electron positron annihilations in the center of mass energy range of 50--65GeV. It provides information between the lower energy facilities such as PEP and PETRA and the new facilities SLC and LEP which are designed to operate in the region of the Z{sup 0} mass near 90GeV. In the region of the AMY experiment, interaction cross sections are near their minimum of about 100pb, making it difficult to acquire large data samples during typical running cycles. This last year hasmore » seen an accumulation of about 10--{minus}12pb{sup {minus}1} of integrated luminosity in the energy range from 58 to 61.7GeV. Despite this limited data sample, the AMY experiment has been extremely active in attempting to extract the minimum amount of information from the data. Some of the most significant results are discussed in this paper. 9 refs.« less

Plasma lens experiments at the Final Focus Test Beam

DOE Office of Scientific and Technical Information (OSTI.GOV)

Barletta, B.; Chattopadhyay, S.; Chen, P.

1993-04-01

We intend to carry out a series of plasma lens experiments at the Final Focus Test Beam facility at SLAC. These experiments will be the first to study the focusing of particle beams by plasma focusing devices in the parameter regime of interest for high energy colliders, and is expected to lead to plasma lens designs capable of unprecedented spot sizes. Plasma focusing of positron beams will be attempted for the first time. We will study the effects of lens aberrations due to various lens imperfections. Several approaches will be applied to create the plasma required including laser ionization andmore » beam ionization of a working gas. At an increased bunch population of 2.5 {times} 10{sup 10}, tunneling ionization of a gas target by an electron beam -- an effect which has never been observed before -- should be significant. The compactness of our device should prove to be of interest for applications at the SLC and the next generation linear colliders.« less

The Effect of Magnetic Field on Positron Range and Spatial Resolution in an Integrated Whole-Body Time-Of-Flight PET/MRI System.

PubMed

Huang, Shih-Ying; Savic, Dragana; Yang, Jaewon; Shrestha, Uttam; Seo, Youngho

2014-11-01

Simultaneous imaging systems combining positron emission tomography (PET) and magnetic resonance imaging (MRI) have been actively investigated. A PET/MR imaging system (GE Healthcare) comprised of a time-of-flight (TOF) PET system utilizing silicon photomultipliers (SiPMs) and 3-tesla (3T) MRI was recently installed at our institution. The small-ring (60 cm diameter) TOF PET subsystem of this PET/MRI system can generate images with higher spatial resolution compared with conventional PET systems. We have examined theoretically and experimentally the effect of uniform magnetic fields on the spatial resolution for high-energy positron emitters. Positron emitters including 18 F, 124 I, and 68 Ga were simulated in water using the Geant4 Monte Carlo toolkit in the presence of a uniform magnetic field (0, 3, and 7 Tesla). The positron annihilation position was tracked to determine the 3D spatial distribution of the 511-keV gammy ray emission. The full-width at tenth maximum (FWTM) of the positron point spread function (PSF) was determined. Experimentally, 18 F and 68 Ga line source phantoms in air and water were imaged with an investigational PET/MRI system and a PET/CT system to investigate the effect of magnetic field on the spatial resolution of PET. The full-width half maximum (FWHM) of the line spread function (LSF) from the line source was determined as the system spatial resolution. Simulations and experimental results show that the in-plane spatial resolution was slightly improved at field strength as low as 3 Tesla, especially when resolving signal from high-energy positron emitters in the air-tissue boundary.

Yogurt fermentation in the presence of starch-lipid composite.

PubMed

Singh, M; Kim, S

2009-03-01

The fermentation of yogurt in the presence of 0.5%, 1.0%, 1.5%, and 2.0% starch-lipid composite (SLC) was investigated. The pH, viscosity, and morphology of the mix were monitored during the fermentation process. The rate of drop in pH with time during incubation was not affected by the addition of SLC. However, it was found that the presence of SLC caused faster aggregation, which was clearly evidenced by the viscosity variation during the process of fermentation. An examination of the morphologies confirmed that aggregation occurred earlier in the presence of SLC and SLC did not form phase-separated domains. This study concludes that SLC would serve as a good additive (fat replacer and stabilizer) for the production of yogurt.

Search for Cosmic-Ray Electron and Positron Anisotropies with Seven Years of Fermi Large Area Telescope Data

DOE PAGES

Abdollahi, S.; Ackermann, M.; Ajello, M.; ...

2017-03-01

We present the Large Area Telescope on board the Fermi Gamma-ray Space Telescope that has collected the largest ever sample of high-energy cosmic-ray electron and positron events since the beginning of its operation. Potential anisotropies in the arrival directions of cosmic-ray electrons or positrons could be a signature of the presence of nearby sources. We use almost seven years of data with energies above 42 GeV processed with the Pass 8 reconstruction. The present data sample can probe dipole anisotropies down to a level of 10 -3. We take into account systematic effects that could mimic true anisotropies at thismore » level. We present a detailed study of the event selection optimization of the cosmic-ray electrons and positrons to be used for anisotropy searches. Since no significant anisotropies have been detected on any angular scale, we present upper limits on the dipole anisotropy. Lastly, the present constraints are among the strongest to date probing the presence of nearby young and middle-aged sources.« less

Electrons in a closed galaxy model of cosmic rays

NASA Technical Reports Server (NTRS)

Ramaty, R.; Westergaard, N. J.

1976-01-01

The consistency of positrons and electrons was studied using a propagation model in which the cosmic rays are stopped by nuclear collisions or energy losses before they can escape from the galaxy (the closed-galaxy model). The fact that no inconsistency was found between the predictions and the data implies that the protons which produce the positrons by nuclear reactions could have their origin in a large number of distant sources, as opposed to the heavier nuclei which in this model come from a more limited set of sources. The closed-galaxy model predicts steep electron and positron spectra at high energies. None of these are inconsistent with present measurements; but future measurements of the spectrum of high-energy positrons could provide a definite test for the model. The closed-galaxy model also predicts that the interstellar electron intensity below a few GeV is larger than that implied by other models. The consequence of this result is that electron bremsstrahlung is responsible for about 50% of the galactic gamma-ray emission at photon energies greater than 100 MeV.

SLC52A2 [p.P141T] and SLC52A3 [p.N21S] causing Brown-Vialetto-Van Laere Syndrome in an Indian patient: First genetically proven case with mutations in two riboflavin transporters

PubMed Central

Udhayabanu, Tamilarasan; Subramanian, Veedamali S; Teafatiller, Trevor; Gowda, Vykuntaraju K; Raghavan, Varun S; Varalakshmi, Perumal; Said, Hamid M; Ashokkumar, Balasubramaniem

2017-01-01

Background Brown-Vialetto-Van Laere Syndrome (BVVLS), a rare neurological disorder characterized by bulbar palsies and sensorineural deafness, is mainly associated with defective riboflavin transporters encoded by the SLC52A2 and SLC52A3 genes. Methods Here we present a 16-year-old BVVLS patient belonging to a five generation consanguineous family from Indian ethnicity with two homozygous missense mutations viz., c.421C>A [p.P141T] in SLC52A2 and c.62A>G [p.N21S] in SLC52A3. Results Functional characterization based on 3H-riboflavin uptake assay and live-cell confocal imaging revealed that the effect of mutation c.421C>A [p.P141T] identified in SLC52A2 had a slight reduction in riboflavin uptake; on the other hand, the c.62A>G [p.N21S] identified in SLC52A3 showed a drastic reduction in riboflavin uptake, which appeared to be due to impaired trafficking and membrane targeting of the hRFVT-3 protein. Conclusions This is the first report presenting mutations in both riboflavin transporters hRFVT-2 and hRFVT-3 in the same BVVLS patient. Also, c.62A>G [p.N21S] in SLC52A3 appears to contribute more to the disease phenotype in this patient than c.421C>A [p.P141T] in SLC52A2. PMID:27702554

Developmental expression of solute carrier family 26A member 4 (SLC26A4/pendrin) during amelogenesis in developing rodent teeth.

PubMed

Bronckers, Antonius L J J; Guo, Jing; Zandieh-Doulabi, Behrouz; Bervoets, Theodore J; Lyaruu, Donacian M; Li, Xiangming; Wangemann, Philine; DenBesten, Pamela

2011-12-01

Ameloblasts need to regulate pH during the formation of enamel crystals, a process that generates protons. Solute carrier family 26A member 4 (SLC26A4, or pendrin) is an anion exchanger for chloride, bicarbonate, iodine, and formate. It is expressed in apical membranes of ion-transporting epithelia in kidney, inner ear, and thyroid where it regulates luminal pH and fluid transport. We hypothesized that maturation ameloblasts express SLC26A4 to neutralize acidification of enamel fluid in forming enamel. In rodents, secretory and maturation ameloblasts were immunopositive for SLC26A4. Staining was particularly strong in apical membranes of maturation ameloblasts facing forming enamel. RT-PCR confirmed the presence of mRNA transcripts for Slc26a4 in enamel organs. SLC26A4 immunostaining was also found in mineralizing connective tissues, including odontoblasts, osteoblasts, osteocytes, osteoclasts, bone lining cells, cellular cementoblasts, and cementocytes. However, Slc26a4-null mutant mice had no overt dental phenotype. The presence of SLC26A4 in apical plasma membranes of maturation ameloblasts is consistent with a potential function as a pH regulator. SLC26A4 does not appear to be critical for ameloblast function and is probably compensated by other pH regulators. © 2011 Eur J Oral Sci.

Beam dynamic simulation and optimization of the CLIC positron source and the capture linac

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bayar, C., E-mail: cafer.bayar@cern.ch; CERN, Geneva; Doebert, S., E-mail: Steffen.Doebert@cern.ch

2016-03-25

The CLIC Positron Source is based on the hybrid target composed of a crystal and an amorphous target. Simulations have been performed from the exit of the amorphous target to the end of pre-injector linac which captures and accelerates the positrons to an energy of 200 MeV. Simulations are performed by the particle tracking code PARMELA. The magnetic field of the AMD is represented in PARMELA by simple coils. Two modes are applied in this study. The first one is accelerating mode based on acceleration after the AMD. The second one is decelerating mode based on deceleration in the first acceleratingmore » structure. It is shown that the decelerating mode gives a higher yield for the e{sup +} beam in the end of the Pre-Injector Linac.« less

Genetic variants in SLC22A17 and SLC22A7 are associated with anthracycline-induced cardiotoxicity in children.

PubMed

Visscher, Henk; Rassekh, S Rod; Sandor, George S; Caron, Huib N; van Dalen, Elvira C; Kremer, Leontien C; van der Pal, Helena J; Rogers, Paul C; Rieder, Michael J; Carleton, Bruce C; Hayden, Michael R; Ross, Colin J

2015-01-01

To identify novel variants associated with anthracycline-induced cardiotoxicity and to assess these in a genotype-guided risk prediction model. Two cohorts treated for childhood cancer (n = 344 and 218, respectively) were genotyped for 4578 SNPs in drug ADME and toxicity genes. Significant associations were identified in SLC22A17 (rs4982753; p = 0.0078) and SLC22A7 (rs4149178; p = 0.0034), with replication in the second cohort (p = 0.0071 and 0.047, respectively). Additional evidence was found for SULT2B1 and several genes related to oxidative stress. Adding the SLC22 variants to the prediction model improved its discriminative ability (AUC 0.78 vs 0.75 [p = 0.029]). Two novel variants in SLC22A17 and SLC22A7 were significantly associated with anthracycline-induced cardiotoxicity and improved a genotype-guided risk prediction model, which could improve patient risk stratification.

NLC Injector Systems

Science.gov Websites

text only NLC Home Page NLC Technical SLAC Sources Damping Rings S & L Band Linacs Engineering ; Presentations Injector System Documentation Talks and Presentations The NLC ZDR ISG Reports Sources Lasers Photocathodes Electron Source Laser Maintenance Facility Positron Source Sources Technical Notes Sources Meeting

SLC2A9 is a high-capacity urate transporter in humans.

PubMed

Caulfield, Mark J; Munroe, Patricia B; O'Neill, Deb; Witkowska, Kate; Charchar, Fadi J; Doblado, Manuel; Evans, Sarah; Eyheramendy, Susana; Onipinla, Abiodun; Howard, Philip; Shaw-Hawkins, Sue; Dobson, Richard J; Wallace, Chris; Newhouse, Stephen J; Brown, Morris; Connell, John M; Dominiczak, Anna; Farrall, Martin; Lathrop, G Mark; Samani, Nilesh J; Kumari, Meena; Marmot, Michael; Brunner, Eric; Chambers, John; Elliott, Paul; Kooner, Jaspal; Laan, Maris; Org, Elin; Veldre, Gudrun; Viigimaa, Margus; Cappuccio, Francesco P; Ji, Chen; Iacone, Roberto; Strazzullo, Pasquale; Moley, Kelle H; Cheeseman, Chris

2008-10-07

Serum uric acid levels in humans are influenced by diet, cellular breakdown, and renal elimination, and correlate with blood pressure, metabolic syndrome, diabetes, gout, and cardiovascular disease. Recent genome-wide association scans have found common genetic variants of SLC2A9 to be associated with increased serum urate level and gout. The SLC2A9 gene encodes a facilitative glucose transporter, and it has two splice variants that are highly expressed in the proximal nephron, a key site for urate handling in the kidney. We investigated whether SLC2A9 is a functional urate transporter that contributes to the longstanding association between urate and blood pressure in man. We expressed both SLC2A9 splice variants in Xenopus laevis oocytes and found both isoforms mediate rapid urate fluxes at concentration ranges similar to physiological serum levels (200-500 microM). Because SLC2A9 is a known facilitative glucose transporter, we also tested whether glucose or fructose influenced urate transport. We found that urate is transported by SLC2A9 at rates 45- to 60-fold faster than glucose, and demonstrated that SLC2A9-mediated urate transport is facilitated by glucose and, to a lesser extent, fructose. In addition, transport is inhibited by the uricosuric benzbromarone in a dose-dependent manner (Ki = 27 microM). Furthermore, we found urate uptake was at least 2-fold greater in human embryonic kidney (HEK) cells overexpressing SLC2A9 splice variants than nontransfected kidney cells. To confirm that our findings were due to SLC2A9, and not another urate transporter, we showed that urate transport was diminished by SLC2A9-targeted siRNA in a second mammalian cell line. In a cohort of men we showed that genetic variants of SLC2A9 are associated with reduced urinary urate clearance, which fits with common variation at SLC2A9 leading to increased serum urate. We found no evidence of association with hypertension (odds ratio 0.98, 95% confidence interval [CI] 0.9 to 1.05, p > 0.33) by meta-analysis of an SLC2A9 variant in six case-control studies including 11,897 participants. In a separate meta-analysis of four population studies including 11,629 participants we found no association of SLC2A9 with systolic (effect size -0.12 mm Hg, 95% CI -0.68 to 0.43, p = 0.664) or diastolic blood pressure (effect size -0.03 mm Hg, 95% CI -0.39 to 0.31, p = 0.82). This study provides evidence that SLC2A9 splice variants act as high-capacity urate transporters and is one of the first functional characterisations of findings from genome-wide association scans. We did not find an association of the SLC2A9 gene with blood pressure in this study. Our findings suggest potential pathogenic mechanisms that could offer a new drug target for gout.

SLC2A9 Is a High-Capacity Urate Transporter in Humans

PubMed Central

O'Neill, Deb; Witkowska, Kate; Charchar, Fadi J; Doblado, Manuel; Evans, Sarah; Eyheramendy, Susana; Onipinla, Abiodun; Howard, Philip; Shaw-Hawkins, Sue; Dobson, Richard J; Wallace, Chris; Newhouse, Stephen J; Brown, Morris; Connell, John M; Dominiczak, Anna; Farrall, Martin; Lathrop, G. Mark; Samani, Nilesh J; Kumari, Meena; Marmot, Michael; Brunner, Eric; Chambers, John; Elliott, Paul; Kooner, Jaspal; Laan, Maris; Org, Elin; Veldre, Gudrun; Viigimaa, Margus; Cappuccio, Francesco P; Ji, Chen; Iacone, Roberto; Strazzullo, Pasquale; Moley, Kelle H; Cheeseman, Chris

2008-01-01

Background Serum uric acid levels in humans are influenced by diet, cellular breakdown, and renal elimination, and correlate with blood pressure, metabolic syndrome, diabetes, gout, and cardiovascular disease. Recent genome-wide association scans have found common genetic variants of SLC2A9 to be associated with increased serum urate level and gout. The SLC2A9 gene encodes a facilitative glucose transporter, and it has two splice variants that are highly expressed in the proximal nephron, a key site for urate handling in the kidney. We investigated whether SLC2A9 is a functional urate transporter that contributes to the longstanding association between urate and blood pressure in man. Methods and Findings We expressed both SLC2A9 splice variants in Xenopus laevis oocytes and found both isoforms mediate rapid urate fluxes at concentration ranges similar to physiological serum levels (200–500 μM). Because SLC2A9 is a known facilitative glucose transporter, we also tested whether glucose or fructose influenced urate transport. We found that urate is transported by SLC2A9 at rates 45- to 60-fold faster than glucose, and demonstrated that SLC2A9-mediated urate transport is facilitated by glucose and, to a lesser extent, fructose. In addition, transport is inhibited by the uricosuric benzbromarone in a dose-dependent manner (K i = 27 μM). Furthermore, we found urate uptake was at least 2-fold greater in human embryonic kidney (HEK) cells overexpressing SLC2A9 splice variants than nontransfected kidney cells. To confirm that our findings were due to SLC2A9, and not another urate transporter, we showed that urate transport was diminished by SLC2A9-targeted siRNA in a second mammalian cell line. In a cohort of men we showed that genetic variants of SLC2A9 are associated with reduced urinary urate clearance, which fits with common variation at SLC2A9 leading to increased serum urate. We found no evidence of association with hypertension (odds ratio 0.98, 95% confidence interval [CI] 0.9 to 1.05, p > 0.33) by meta-analysis of an SLC2A9 variant in six case–control studies including 11,897 participants. In a separate meta-analysis of four population studies including 11,629 participants we found no association of SLC2A9 with systolic (effect size −0.12 mm Hg, 95% CI −0.68 to 0.43, p = 0.664) or diastolic blood pressure (effect size −0.03 mm Hg, 95% CI −0.39 to 0.31, p = 0.82). Conclusions This study provides evidence that SLC2A9 splice variants act as high-capacity urate transporters and is one of the first functional characterisations of findings from genome-wide association scans. We did not find an association of the SLC2A9 gene with blood pressure in this study. Our findings suggest potential pathogenic mechanisms that could offer a new drug target for gout. PMID:18842065

Positron kinetics in an idealized PET environment

PubMed Central

Robson, R. E.; Brunger, M. J.; Buckman, S. J.; Garcia, G.; Petrović, Z. Lj.; White, R. D.

2015-01-01

The kinetic theory of non-relativistic positrons in an idealized positron emission tomography PET environment is developed by solving the Boltzmann equation, allowing for coherent and incoherent elastic, inelastic, ionizing and annihilating collisions through positronium formation. An analytic expression is obtained for the positronium formation rate, as a function of distance from a spherical source, in terms of the solutions of the general kinetic eigenvalue problem. Numerical estimates of the positron range - a fundamental limitation on the accuracy of PET, are given for positrons in a model of liquid water, a surrogate for human tissue. Comparisons are made with the ‘gas-phase’ assumption used in current models in which coherent scattering is suppressed. Our results show that this assumption leads to an error of the order of a factor of approximately 2, emphasizing the need to accurately account for the structure of the medium in PET simulations. PMID:26246002

High-resolution Auger-electron spectroscopy induced by positron annihilation on Fe, Ni, Cu, Zn, Pd, and Au

NASA Astrophysics Data System (ADS)

Hugenschmidt, C.; Mayer, J.; Schreckenbach, K.

2010-04-01

Positron annihilation induced Auger electron spectroscopy (PAES) enables almost background free, non-destructive surface analysis with high surface selectivity. The Auger-spectrometer at the high intense positron source NEPOMUC now allows to record positron annihilation induced Auger spectra within a short data acquisition time of 10-80 minutes. With a new hemispherical electron energy analyzer and due to the exceptional peak to noise ratio, we succeeded to measure Auger-transitions such as the M2,3V V double peak of nickel with high energy resolution. The relative Auger-electron intensities are obtained by the analysis of the recorded positron annihilation induced Auger spectra for the surfaces of Fe, Ni, Cu, Pd and Au. It is demonstrated, that high-resolution PAES allows to determine experimentally the relative surface core annihilation probability of various atomic levels.

High-field penning-malmberg trap: confinement properties and use in positron accumulation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hartley, J.H.

1997-09-01

This dissertation reports on the development of the 60 kG cryogenic positron trap at Lawrence Livermore National Laboratory, and compares the trap`s confinement properties with other nonneutral plasma devices. The device is designed for the accumulation of up to 2{times}10{sup 9} positrons from a linear-accelerator source. This positron plasma could then be used in Bhabha scattering experiments. Initial efforts at time-of-flight accumulation of positrons from the accelerator show rapid ({approximately}100 ms) deconfinement, inconsistent with the long electron lifetimes. Several possible deconfinement mechanisms have been explored, including annihilation on residual gas, injection heating, rf noise from the accelerator, magnet field curvature,more » and stray fields. Detailed studies of electron confinement demonstrate that the empirical scaling law used to design the trap cannot be extrapolated into the parameter regime of this device. Several possible methods for overcoming these limitations are presented.« less

Nonlinear excitations for the positron acoustic shock waves in dissipative nonextensive electron-positron-ion plasmas

NASA Astrophysics Data System (ADS)

Saha, Asit

2017-03-01

Positron acoustic shock waves (PASHWs) in unmagnetized electron-positron-ion (e-p-i) plasmas consisting of mobile cold positrons, immobile positive ions, q-nonextensive distributed electrons, and hot positrons are studied. The cold positron kinematic viscosity is considered and the reductive perturbation technique is used to derive the Burgers equation. Applying traveling wave transformation, the Burgers equation is transformed to a one dimensional dynamical system. All possible vector fields corresponding to the dynamical system are presented. We have analyzed the dynamical system with the help of potential energy, which helps to identify the stability and instability of the equilibrium points. It is found that the viscous force acting on cold mobile positron fluid is a source of dissipation and is responsible for the formation of the PASHWs. Furthermore, fully nonlinear arbitrary amplitude positron acoustic waves are also studied applying the theory of planar dynamical systems. It is also observed that the fundamental features of the small amplitude and arbitrary amplitude PASHWs are significantly affected by the effect of the physical parameters q e , q h , μ e , μ h , σ , η , and U. This work can be useful to understand the qualitative changes in the dynamics of nonlinear small amplitude and fully nonlinear arbitrary amplitude PASHWs in solar wind, ionosphere, lower part of magnetosphere, and auroral acceleration regions.

Na+-taurocholate cotransporting polypeptide (NTCP/SLC10A1) ortholog in the marine skate Leucoraja erinacea is not a physiological bile salt transporter.

PubMed

Yu, Dongke; Zhang, Han; Lionarons, Daniel A; Boyer, James L; Cai, Shi-Ying

2017-04-01

The Na + -dependent taurocholate cotransporting polypeptide (NTCP/SLC10A1) is a hepatocyte-specific solute carrier, which plays an important role in maintaining bile salt homeostasis in mammals. The absence of a hepatic Na + -dependent bile salt transport system in marine skate and rainbow trout raises a question regarding the function of the Slc10a1 gene in these species. Here, we have characterized the Slc10a1 gene in the marine skate, Leucoraja erinacea The transcript of skate Slc10a1 (skSlc10a1) encodes 319 amino acids and shares 46% identity to human NTCP (hNTCP) with similar topology to mammalian NTCP. SkSlc10a1 mRNA was mostly confined to the brain and testes with minimal expression in the liver. An FXR-bile salt reporter assay indicated that skSlc10a1 transported taurocholic acid (TCA) and scymnol sulfate, but not as effectively as hNTCP. An [ 3 H]TCA uptake assay revealed that skSlc10a1 functioned as a Na + -dependent transporter, but with low affinity for TCA ( K m = 92.4 µM) and scymnol sulfate ( K i = 31 µM), compared with hNTCP (TCA, K m = 5.4 µM; Scymnol sulfate, K i = 3.5 µM). In contrast, the bile salt concentration in skate plasma was 2 µM, similar to levels seen in mammals. Interestingly, skSlc10a1 demonstrated transport activity for the neurosteroids dehydroepiandrosterone sulfate and estrone-3-sulfate at physiological concentration, similar to hNTCP. Together, our findings indicate that skSlc10a1 is not a physiological bile salt transporter, providing a molecular explanation for the absence of a hepatic Na + -dependent bile salt uptake system in skate. We speculate that Slc10a1 is a neurosteroid transporter in skate that gained its substrate specificity for bile salts later in vertebrate evolution. Copyright © 2017 the American Physiological Society.

The Physiological Effects of Deleting the Mouse Slc30a8 Gene Encoding Zinc Transporter-8 Are Influenced by Gender and Genetic Background

PubMed Central

Pound, Lynley D.; Sarkar, Suparna A.; Ustione, Alessandro; Dadi, Prasanna K.; Shadoan, Melanie K.; Lee, Catherine E.; Walters, Jay A.; Shiota, Masakazu; McGuinness, Owen P.; Jacobson, David A.; Piston, David W.; Hutton, John C.; Powell, David R.; O’Brien, Richard M.

2012-01-01

Objective The SLC30A8 gene encodes the islet-specific transporter ZnT-8, which is hypothesized to provide zinc for insulin-crystal formation. A polymorphic variant in SLC30A8 is associated with altered susceptibility to type 2 diabetes. Several groups have examined the effect of global Slc30a8 gene deletion but the results have been highly variable, perhaps due to the mixed 129SvEv/C57BL/6J genetic background of the mice studied. We therefore sought to remove the conflicting effect of 129SvEv-specific modifier genes. Methods The impact of Slc30a8 deletion was examined in the context of the pure C57BL/6J genetic background. Results Male C57BL/6J Slc30a8 knockout (KO) mice had normal fasting insulin levels and no change in glucose-stimulated insulin secretion (GSIS) from isolated islets in marked contrast to the ∼50% and ∼35% decrease, respectively, in both parameters observed in male mixed genetic background Slc30a8 KO mice. This observation suggests that 129SvEv-specific modifier genes modulate the impact of Slc30a8 deletion. In contrast, female C57BL/6J Slc30a8 KO mice had reduced (∼20%) fasting insulin levels, though this was not associated with a change in fasting blood glucose (FBG), or GSIS from isolated islets. This observation indicates that gender also modulates the impact of Slc30a8 deletion, though the physiological explanation as to why impaired insulin secretion is not accompanied by elevated FBG is unclear. Neither male nor female C57BL/6J Slc30a8 KO mice showed impaired glucose tolerance. Conclusions Our data suggest that, despite a marked reduction in islet zinc content, the absence of ZnT-8 does not have a substantial impact on mouse physiology. PMID:22829903

Human SLC4A11-C functions as a DIDS-stimulatable H+(OH−) permeation pathway: partial correction of R109H mutant transport

PubMed Central

Kao, Liyo; Azimov, Rustam; Abuladze, Natalia; Newman, Debra

2014-01-01

The SLC4A11 gene mutations cause a variety of genetic corneal diseases, including congenital hereditary endothelial dystrophy 2 (CHED2), Harboyan syndrome, some cases of Fuchs' endothelial dystrophy (FECD), and possibly familial keratoconus. Three NH2-terminal variants of the human SLC4A11 gene, named SLC4A11-A, -B, and -C are known. The SLC4A11-B variant has been the focus of previous studies. Both the expression of the SLC4A11-C variant in the cornea and its functional properties have not been characterized, and therefore its potential pathophysiological role in corneal diseases remains to be explored. In the present study, we demonstrate that SLC4A11-C is the predominant SLC4A11 variant expressed in human corneal endothelial mRNA and that the transporter functions as an electrogenic H+(OH−) permeation pathway. Disulfonic stilbenes, including 4,4′-diisothiocyano-2,2′-stilbenedisulfonate (DIDS), 4,4′-diisothiocyanatodihydrostilbene-2,2′-disulfonate (H2DIDS), and 4-acetamido-4′-isothiocyanato-stilbene-2,2′-disulfonate (SITS), which are known to bind covalently, increased SLC4A11-C-mediated H+(OH−) flux by 150–200% without having a significant effect in mock-transfected cells. Noncovalently interacting 4,4′-diaminostilbene-2,2′-disulfonate (DADS) was without effect. We tested the efficacy of DIDS on the functionally impaired R109H mutant (SLC4A11-C numbering) that causes CHED2. DIDS (1 mM) increased H+(OH−) flux through the mutant transporter by ∼40–90%. These studies provide a basis for future testing of more specific chemically modified dilsulfonic stilbenes as potential therapeutic agents to improve the functional impairment of specific SLC4A11 mutant transporters. PMID:25394471

Di- and tripeptide transport in vertebrates: the contribution of teleost fish models.

PubMed

Verri, Tiziano; Barca, Amilcare; Pisani, Paola; Piccinni, Barbara; Storelli, Carlo; Romano, Alessandro

2017-04-01

Solute Carrier 15 (SLC15) family, alias H + -coupled oligopeptide cotransporter family, is a group of membrane transporters known for their role in the cellular uptake of di- and tripeptides (di/tripeptides) and peptide-like molecules. Of its members, SLC15A1 (PEPT1) chiefly mediates intestinal absorption of luminal di/tripeptides from dietary protein digestion, while SLC15A2 (PEPT2) mainly allows renal tubular reabsorption of di/tripeptides from ultrafiltration, SLC15A3 (PHT2) and SLC15A4 (PHT1) possibly interact with di/tripeptides and histidine in certain immune cells, and SLC15A5 has unknown function. Our understanding of this family in vertebrates has steadily increased, also due to the surge of genomic-to-functional information from 'non-conventional' animal models, livestock, poultry, and aquaculture fish species. Here, we review the literature on the SLC15 transporters in teleost fish with emphasis on SLC15A1 (PEPT1), one of the solute carriers better studied amongst teleost fish because of its relevance in animal nutrition. We report on the operativity of the transporter, the molecular diversity, and multiplicity of structural-functional solutions of the teleost fish orthologs with respect to higher vertebrates, its relevance at the intersection of the alimentary and osmoregulative functions of the gut, its response under various physiological states and dietary solicitations, and its possible involvement in examples of total body plasticity, such as growth and compensatory growth. By a comparative approach, we also review the few studies in teleost fish on SLC15A2 (PEPT2), SLC15A4 (PHT1), and SLC15A3 (PHT2). By representing the contribution of teleost fish to the knowledge of the physiology of di/tripeptide transport and transporters, we aim to fill the gap between higher and lower vertebrates.

Transport via SLC5A8 (SMCT1) Is Obligatory for 2-Oxothiazolidine-4-Carboxylate to Enhance Glutathione Production in Retinal Pigment Epithelial Cells

PubMed Central

Babu, Ellappan; Ananth, Sudha; Veeranan-Karmegam, Rajalakshmi; Coothankandaswamy, Veena; Smith, Sylvia B.; Boettger, Thomas; Ganapathy, Vadivel

2011-01-01

Purpose. To evaluate the role of SLC5A8 in the transport of 2-oxothiazolidine-4-carboxylate (OTC) and to determine whether OTC augments glutathione production in RPE cells, thereby providing protection against oxidative stress. Methods. SLC5A8-mediated transport of OTC was monitored in Xenopus laevis oocytes by electrophysiological means. Saturation kinetics, Na+-activation kinetics, and inhibition by ibuprofen were analyzed by monitoring OTC-induced currents as a measure of transport activity. Oxidative stress was induced in ARPE-19 cells and primary RPE cells isolated from wild type and Slc5a8-/- mouse retinas using H2O2, and the effects of OTC on cell death and intracellular glutathione concentration were examined. Results. Heterologous expression of human SLC5A8 in X. laevis oocytes induced Na+-dependent inward currents in the presence of OTC under voltage-clamp conditions. The transport of OTC via SLC5A8 was saturable, with a Kt of 104 ± 3 μM. The Na+-activation kinetics was sigmoidal with a Hill coefficient of 1.9 ± 0.1, suggesting involvement of two Na+ in the activation process. Ibuprofen, a blocker of SLC5A8, inhibited SLC5A8-mediated OTC transport; the concentration necessary for half-maximal inhibition was 17 ± 1 μM. OTC increased glutathione levels and protected ARPE-19 and primary RPE cells isolated from wild type mouse retinas from H2O2-induced cell death. These effects were abolished in primary RPE isolated from Slc5a8-/- mouse retinas. Conclusions. OTC is a transportable substrate for SLC5A8. OTC augments glutathione production in RPE cells, thereby protecting them from oxidative damage. Transport via SLC5A8 is obligatory for this process. PMID:21508099

The effects of reduced dietary protein level on amino acid transporters and mTOR signaling pathway in pigs.

PubMed

Wang, Dan; Wan, Xuebin; Peng, Jian; Xiong, Qi; Niu, Hongdan; Li, Huanan; Chai, Jin; Jiang, Siwen

2017-04-01

Amino acid transporter plays an important role in regulating mTOR signaling pathway. This study investigated the effects of reduced dietary protein levels on amino acid transporters and mTOR signaling pathway. A total of 54 weaning pigs were randomly allocated into a 3 × 3 factorial design, followed by slaughtering the pigs separately after 10-, 25- and 45-day feeding, with 18 pigs from each feeding period divided into three subgroups for treatment with three different protein-level diets: 20% crude protein (CP) diet (normal recommended, high protein, HP), 17% CP diet (medium protein, MP) and 14% CP diet (low protein, LP). The results indicated that reduced dietary protein level decreased the weight of longissimus dorsi. Additionally, quantitative PCR chip analysis showed that mRNA expression of amino acid transporters SLC38A2, SLC1A7, SLC7A1, SLC7A5, SLC16A10 and SLC3A2 in the LP group were significantly (P < 0.05) higher than those in the MP or HP group, and the phosphorylation of mTOR and S6K1 decreased in the LP group after 25-day feeding. Furthermore, the vitro experimental results further confirmed that the mRNA levels for SLC7A1, SLC7A5, SLC3A2, SLC38A2 and SLC36A1 were increased and the phosphorylation of mTOR and S6K1 was decreased when the concentration of amino acids in C2C12 myoblasts was reduced. All these results indicated that the LP diet induced a high expression of amino acid transporters and the inhibition of the mTOR activity, which resulting in restriction on protein synthesis and longissimus dorsi growth. Copyright © 2017 Elsevier Inc. All rights reserved.

SLC3A1 and SLC7A9 mutations in autosomal recessive or dominant canine cystinuria: a new classification system.

PubMed

Brons, A-K; Henthorn, P S; Raj, K; Fitzgerald, C A; Liu, J; Sewell, A C; Giger, U

2013-01-01

Cystinuria, one of the first recognized inborn errors of metabolism, has been reported in many dog breeds. To determine urinary cystine concentrations, inheritance, and mutations in the SLC3A1 and SLC7A9 genes associated with cystinuria in 3 breeds. Mixed and purebred Labrador Retrievers (n = 6), Australian Cattle Dogs (6), Miniature Pinschers (4), and 1 mixed breed dog with cystine urolithiasis, relatives and control dogs. Urinary cystinuria and aminoaciduria was assessed and exons of the SLC3A1 and SLC7A9 genes were sequenced from genomic DNA. In each breed, male and female dogs, independent of neuter status, were found to form calculi. A frameshift mutation in SLC3A1 (c.350delG) resulting in a premature stop codon was identified in autosomal-recessive (AR) cystinuria in Labrador Retrievers and mixed breed dogs. A 6 bp deletion (c.1095_1100del) removing 2 threonines in SLC3A1 was found in autosomal-dominant (AD) cystinuria with a more severe phenotype in homozygous than in heterozygous Australian Cattle Dogs. A missense mutation in SLC7A9 (c.964G>A) was discovered in AD cystinuria in Miniature Pinschers with only heterozygous affected dogs observed to date. Breed-specific DNA tests were developed, but the prevalence of each mutation remains unknown. These studies describe the first AD inheritance and the first putative SLC7A9 mutation to cause cystinuria in dogs and expand our understanding of this phenotypically and genetically heterogeneous disease, leading to a new classification system for canine cystinuria and better therapeutic management and genetic control in these breeds. Copyright © 2013 by the American College of Veterinary Internal Medicine.

Recovered insulin production after thiamine administration in permanent neonatal diabetes mellitus with a novel solute carrier family 19 member 2 (SLC19A2) mutation.

PubMed

Sun, Chengjun; Pei, Zhou; Zhang, Miaoying; Sun, Bijun; Yang, Lin; Zhao, Zhuhui; Cheng, Ruoqian; Luo, Feihong

2018-01-01

Solute carrier family 19 member 2 (SLC19A2) gene deficiency is one of the causes of permanent neonatal diabetes mellitus (PNDM) and can be effectively managed by thiamine supplementation. Herein we report on a male patient with a novel SLC19A2 mutation and summarize the clinical characteristics of patients with SLC19A2 deficiency. The genetic diagnosis of the patient with PNDM was made by sequencing and quantitative polymerase chain reaction. The clinical characteristics of PNDM were summarized on the basis of a systematic review of the literature. The patient with PNDM had c.848G>A (p.W283X) homozygous mutation in SLC19A2. His father had a wild-type SLC19A2 (c.848G) and his mother was c.848G/A heterozygous. The patient and his father both had a diploid genotype (c.848A/A and c.848G/G). After oral thiamine administration, the patient's fasting C-peptide levels increased gradually, and there was a marked decrease in insulin requirements. A search of the literature revealed that thiamine treatment was effective and improved diabetes in 63% of patients with SLC19A2 deficiency. A novel SLC19A2 mutation (c.848G>A; p.W283X) was identified, which was most likely inherited as segmental uniparental isodisomy. Insulin insufficiency in PNDM caused by SLC19A2 deficiency can be corrected by thiamine supplementation. The differential diagnosis of SLC19A2 deficiency should be considered in children with PNDM accompanied by anemia or hearing defects to allow for early treatment. © 2017 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

Mouse Slc4a11 expressed in Xenopus oocytes is an ideally selective H+/OH− conductance pathway that is stimulated by rises in intracellular and extracellular pH

PubMed Central

Myers, Evan J.; Marshall, Aniko; Jennings, Michael L.

2016-01-01

The SLC4A11 gene encodes the bicarbonate-transporter-related protein BTR1, which is mutated in syndromes characterized by vision and hearing loss. Signs of these diseases [congenital hereditary endothelial dystrophy (CHED) and Harboyan syndrome] are evident in mouse models of Slc4a11 disruption. However, the intrinsic activity of Slc4a11 remains controversial, complicating assignment of its (patho)physiological role. Most studies concur that Slc4a11 transports H+ (or the thermodynamically equivalent species OH−) rather than HCO3−, but disparities have arisen as to whether the transport is coupled to another species such as Na+ or NH3/NH4+. Here for the first time, we examine the action of mouse Slc4a11 in Xenopus oocytes. We simultaneously monitor changes in intracellular pH, membrane potential, and conductance as we alter extracellular pH, revealing the electrical and chemical driving forces that underlie the observed ion fluxes. We find that mSlc4a11 is an ideally selective H+/OH− conductive pathway, the action of which is uncoupled from the cotransport of any other ion. We also find that the activity of mSlc4a11 is independently enhanced by both extracellular and intracellular alkalinization, suggesting OH− as the most likely substrate and providing a novel explanation for the apparent NH3-dependence of Slc4a11-mediated currents reported by others. We suggest that the unique properties of Slc4a11 action underlie its value as a pH regulator in corneal endothelial cells. PMID:27681179

Interaction among variants in the SLC gene family (SLC6A14, SLC26A9, SLC11A1, and SLC9A3) and CFTR mutations with clinical markers of cystic fibrosis.

PubMed

Pereira, Stephanie V N; Ribeiro, Jose D; Bertuzzo, Carmen S; Marson, Fernando A L

2018-04-10

Cystic fibrosis (CF) is due to dysfunction of the CFTR channel and function of this channel is, in turn, affected by modifier genes that can impact the clinical phenotype. In this context, we analyzed the interaction among rs3788766*SLC6A14, rs7512462*SLC26A9, rs17235416*SLC11A1, and rs17563161*SLC9A3 variants, CFTR mutations and 40 CF severity markers by the Multifactor Dimensionality Reduction (MDR) model. A total of 164 patients with CF were included in the study. The variants in the modifier genes were identified by real-time PCR and the genotype of the CFTR gene in the diagnostic routine. Analysis of interaction between variants, CFTR mutations groupings and demographic, clinical and laboratory data were performed by the MDR. There were interaction between the rs3788766, rs7512462, rs17235416, and rs17563161 variants, and CFTR mutations with pancreatic insufficiency (PI), onset of digestive symptoms, and presence of mucoid Pseudomonas aeruginosa. Regarding PI, the interaction was observed for CFTR*rs17563161 (P-value = 0.015). Also, for onset of digestive symptoms the interaction was observed for CFTR*rs3788766*rs7512462*rs17235416*rs17563161 (P-value = 0.036). Considering the presence of mucoid P. aeruginosa, the interaction occurred for CFTR*rs3788766*rs7512462*rs17563161 (P-value = 0.035). Interaction between variants in the SLC family genes and the grouping for CFTR mutations were associated with PI, onset of digestive symptoms and mucoid P. aeruginosa, being important to determine one of the factors that may cause the diversity among the patients with CF. © 2018 Wiley Periodicals, Inc.

SLC52A2 [p.P141T] and SLC52A3 [p.N21S] causing Brown-Vialetto-Van Laere Syndrome in an Indian patient: First genetically proven case with mutations in two riboflavin transporters.

PubMed

Udhayabanu, Tamilarasan; Subramanian, Veedamali S; Teafatiller, Trevor; Gowda, Vykuntaraju K; Raghavan, Varun S; Varalakshmi, Perumal; Said, Hamid M; Ashokkumar, Balasubramaniem

2016-11-01

Brown-Vialetto-Van Laere Syndrome (BVVLS), a rare neurological disorder characterized by bulbar palsies and sensorineural deafness, is mainly associated with defective riboflavin transporters encoded by the SLC52A2 and SLC52A3 genes. Here we present a 16-year-old BVVLS patient belonging to a five generation consanguineous family from Indian ethnicity with two homozygous missense mutations viz., c.421C>A [p.P141T] in SLC52A2 and c.62A>G [p.N21S] in SLC52A3. Functional characterization based on 3 H-riboflavin uptake assay and live-cell confocal imaging revealed that the effect of mutation c.421C>A [p.P141T] identified in SLC52A2 had a slight reduction in riboflavin uptake; on the other hand, the c.62A>G [p.N21S] identified in SLC52A3 showed a drastic reduction in riboflavin uptake, which appeared to be due to impaired trafficking and membrane targeting of the hRFVT-3 protein. This is the first report presenting mutations in both riboflavin transporters hRFVT-2 and hRFVT-3 in the same BVVLS patient. Also, c.62A>G [p.N21S] in SLC52A3 appears to contribute more to the disease phenotype in this patient than c.421C>A [p.P141T] in SLC52A2. Copyright © 2016 Elsevier B.V. All rights reserved.

SLC4A11 Prevents Osmotic Imbalance Leading to Corneal Endothelial Dystrophy, Deafness, and Polyuria*

PubMed Central

Gröger, Nicole; Fröhlich, Henning; Maier, Hannes; Olbrich, Andrea; Kostin, Sawa; Braun, Thomas; Boettger, Thomas

2010-01-01

Maintenance of ion concentration gradients is essential for the function of many organs, including the kidney, the cornea, and the inner ear. Ion concentrations and fluid content in the cornea are regulated by endothelial cells that separate the collagenous avascular corneal stroma from the anterior eye chamber. Failure to maintain correct ion concentrations leads to swelling and destruction of the cornea. In the inner ear, the stria vascularis is responsible for generating proper ion concentrations in the endolymph, which is essential for hearing. Mutations of SLC4A11 in humans lead to syndromes associated with corneal dystrophy and perceptive deafness. The molecular mechanisms underlying these symptoms are poorly understood, impeding therapeutic interventions. The ion transporter SLC4A11 mediates sodium-dependent transport of borate as well as flux of sodium and hydroxyl ions in vitro. Here, we show that SLC4A11 is expressed in the endothelial cells of the cornea where it prevents severe morphological changes of the cornea caused by increased sodium chloride concentrations in the stroma. In the inner ear, SLC4A11 is located in fibrocytes underlying the stria vascularis. Loss of SLC4A11 leads to morphological changes in the fibrocytes and deafness. We demonstrate that SLC4A11 is essential for the generation of the endocochlear potential but not for regulation of potassium concentrations in the endolymph. In the kidney, SLC4A11 is expressed in the thin descending limb of Henle loop. SLC4A11 is essential for urinary concentration, suggesting that SLC4A11 participates in the countercurrent multiplication that concentrates urine in the kidney medulla. PMID:20185830

Cystic fibrosis gene modifier SLC26A9 modulates airway response to CFTR-directed therapeutics.

PubMed

Strug, Lisa J; Gonska, Tanja; He, Gengming; Keenan, Katherine; Ip, Wan; Boëlle, Pierre-Yves; Lin, Fan; Panjwani, Naim; Gong, Jiafen; Li, Weili; Soave, David; Xiao, Bowei; Tullis, Elizabeth; Rabin, Harvey; Parkins, Michael D; Price, April; Zuberbuhler, Peter C; Corvol, Harriet; Ratjen, Felix; Sun, Lei; Bear, Christine E; Rommens, Johanna M

2016-10-15

Cystic fibrosis is realizing the promise of personalized medicine. Recent advances in drug development that target the causal CFTR directly result in lung function improvement, but variability in response is demanding better prediction of outcomes to improve management decisions. The genetic modifier SLC26A9 contributes to disease severity in the CF pancreas and intestine at birth and here we assess its relationship with disease severity and therapeutic response in the airways. SLC26A9 association with lung disease was assessed in individuals from the Canadian and French CF Gene Modifier consortia with CFTR-gating mutations and in those homozygous for the common Phe508del mutation. Variability in response to a CFTR-directed therapy attributed to SLC26A9 genotype was assessed in Canadian patients with gating mutations. A primary airway model system determined if SLC26A9 shows modification of Phe508del CFTR function upon treatment with a CFTR corrector. In those with gating mutations that retain cell surface-localized CFTR we show that SLC26A9 modifies lung function while this is not the case in individuals homozygous for Phe508del where cell surface expression is lacking. Treatment response to ivacaftor, which aims to improve CFTR-channel opening probability in patients with gating mutations, shows substantial variability in response, 28% of which can be explained by rs7512462 in SLC26A9 (P = 0.0006). When homozygous Phe508del primary bronchial cells are treated to restore surface CFTR, SLC26A9 likewise modifies treatment response (P = 0.02). Our findings indicate that SLC26A9 airway modification requires CFTR at the cell surface, and that a common variant in SLC26A9 may predict response to CFTR-directed therapeutics.

Identification of Mutations in SLC24A4, Encoding a Potassium-Dependent Sodium/Calcium Exchanger, as a Cause of Amelogenesis Imperfecta

PubMed Central

Parry, David A.; Poulter, James A.; Logan, Clare V.; Brookes, Steven J.; Jafri, Hussain; Ferguson, Christopher H.; Anwari, Babra M.; Rashid, Yasmin; Zhao, Haiqing; Johnson, Colin A.; Inglehearn, Chris F.; Mighell, Alan J.

2013-01-01

A combination of autozygosity mapping and exome sequencing identified a null mutation in SLC24A4 in a family with hypomineralized amelogenesis imperfect a (AI), a condition in which tooth enamel formation fails. SLC24A4 encodes a calcium transporter upregulated in ameloblasts during the maturation stage of amelogenesis. Screening of further AI families identified a missense mutation in the ion-binding site of SLC24A4 expected to severely diminish or abolish the ion transport function of the protein. Furthermore, examination of previously generated Slc24a4 null mice identified a severe defect in tooth enamel that reflects impaired amelogenesis. These findings support a key role for SLC24A4 in calcium transport during enamel formation. PMID:23375655

The Solute Carrier Families Have a Remarkably Long Evolutionary History with the Majority of the Human Families Present before Divergence of Bilaterian Species

PubMed Central

Höglund, Pär J.; Nordström, Karl J.V.; Schiöth, Helgi B.; Fredriksson, Robert

2011-01-01

The Solute Carriers (SLCs) are membrane proteins that regulate transport of many types of substances over the cell membrane. The SLCs are found in at least 46 gene families in the human genome. Here, we performed the first evolutionary analysis of the entire SLC family based on whole genome sequences. We systematically mined and analyzed the genomes of 17 species to identify SLC genes. In all, we identified 4,813 SLC sequences in these genomes, and we delineated the evolutionary history of each of the subgroups. Moreover, we also identified ten new human sequences not previously classified as SLCs, which most likely belong to the SLC family. We found that 43 of the 46 SLC families found in Homo sapiens were also found in Caenorhabditis elegans, whereas 42 of them were also found in insects. Mammals have a higher number of SLC genes in most families, perhaps reflecting important roles for these in central nervous system functions. This study provides a systematic analysis of the evolutionary history of the SLC families in Eukaryotes showing that the SLC superfamily is ancient with multiple branches that were present before early divergence of Bilateria. The results provide foundation for overall classification of SLC genes and are valuable for annotation and prediction of substrates for the many SLCs that have not been tested in experimental transport assays. PMID:21186191

SLC26A9-mediated chloride secretion prevents mucus obstruction in airway inflammation

PubMed Central

Anagnostopoulou, Pinelopi; Riederer, Brigitte; Duerr, Julia; Michel, Sven; Binia, Aristea; Agrawal, Raman; Liu, Xuemei; Kalitzki, Katrin; Xiao, Fang; Chen, Mingmin; Schatterny, Jolanthe; Hartmann, Dorothee; Thum, Thomas; Kabesch, Michael; Soleimani, Manoocher; Seidler, Ursula; Mall, Marcus A.

2012-01-01

Asthma is a chronic condition with unknown pathogenesis, and recent evidence suggests that enhanced airway epithelial chloride (Cl–) secretion plays a role in the disease. However, the molecular mechanism underlying Cl– secretion and its relevance in asthma pathophysiology remain unknown. To determine the role of the solute carrier family 26, member 9 (SLC26A9) Cl– channel in asthma, we induced Th2-mediated inflammation via IL-13 treatment in wild-type and Slc26a9-deficient mice and compared the effects on airway ion transport, morphology, and mucus content. We found that IL-13 treatment increased Cl– secretion in the airways of wild-type but not Slc26a9-deficient mice. While IL-13–induced mucus overproduction was similar in both strains, treated Slc26a9-deficient mice exhibited airway mucus obstruction, which did not occur in wild-type controls. In a study involving healthy children and asthmatics, a polymorphism in the 3′ UTR of SLC26A9 that reduced protein expression in vitro was associated with asthma. Our data demonstrate that the SLC26A9 Cl– channel is activated in airway inflammation and suggest that SLC26A9-mediated Cl– secretion is essential for preventing airway obstruction in allergic airway disease. These results indicate that SLC26A9 may serve as a therapeutic target for airway diseases associated with mucus plugging. PMID:22945630

A critical role of solute carrier 22a14 in sperm motility and male fertility in mice

PubMed Central

Maruyama, Shin-ya; Ito, Momoe; Ikami, Yuusuke; Okitsu, Yu; Ito, Chizuru; Toshimori, Kiyotaka; Fujii, Wataru; Yogo, Keiichiro

2016-01-01

We previously identified solute carrier 22a14 (Slc22a14) as a spermatogenesis-associated transmembrane protein in mice. Although Slc22a14 is a member of the organic anion/cation transporter family, its expression profile and physiological role have not been elucidated. Here, we show that Slc22a14 is crucial for sperm motility and male fertility in mice. Slc22a14 is expressed specifically in male germ cells, and mice lacking the Slc22a14 gene show severe male infertility. Although the overall differentiation of sperm was normal, Slc22a14−/− cauda epididymal spermatozoa showed reduced motility with abnormal flagellar bending. Further, the ability to migrate into the female reproductive tract and fertilise the oocyte were also impaired in Slc22a14−/− spermatozoa. The abnormal flagellar bending was thought to be partly caused by osmotic cell swelling since osmotic challenge or membrane permeabilisation treatment alleviated the tail abnormality. In addition, we found structural abnormalities in Slc22a14−/− sperm cells: the annulus, a ring-like structure at the mid-piece–principal piece junction, was disorganised, and expression and localisation of septin 4, an annulus component protein that is essential for the annulus formation, was also impaired. Taken together, our results demonstrated that Slc22a14 plays a pivotal role in normal flagellar structure, motility and fertility in mouse spermatozoa. PMID:27811987

The Zinc Transporter SLC39A13/ZIP13 Is Required for Connective Tissue Development; Its Involvement in BMP/TGF-β Signaling Pathways

PubMed Central

Shimoda, Shinji; Mishima, Kenji; Higashiyama, Hiroyuki; Idaira, Yayoi; Asada, Yoshinobu; Kitamura, Hiroshi; Yamasaki, Satoru; Hojyo, Shintaro; Nakayama, Manabu; Ohara, Osamu; Koseki, Haruhiko; dos Santos, Heloisa G.; Bonafe, Luisa; Ha-Vinh, Russia; Zankl, Andreas; Unger, Sheila; Kraenzlin, Marius E.; Beckmann, Jacques S.; Saito, Ichiro; Rivolta, Carlo; Ikegawa, Shiro; Superti-Furga, Andrea; Hirano, Toshio

2008-01-01

Background Zinc (Zn) is an essential trace element and it is abundant in connective tissues, however biological roles of Zn and its transporters in those tissues and cells remain unknown. Methodology/Principal Findings Here we report that mice deficient in Zn transporter Slc39a13/Zip13 show changes in bone, teeth and connective tissue reminiscent of the clinical spectrum of human Ehlers-Danlos syndrome (EDS). The Slc39a13 knockout (Slc39a13-KO) mice show defects in the maturation of osteoblasts, chondrocytes, odontoblasts, and fibroblasts. In the corresponding tissues and cells, impairment in bone morphogenic protein (BMP) and TGF-β signaling were observed. Homozygosity for a SLC39A13 loss of function mutation was detected in sibs affected by a unique variant of EDS that recapitulates the phenotype observed in Slc39a13-KO mice. Conclusions/Significance Hence, our results reveal a crucial role of SLC39A13/ZIP13 in connective tissue development at least in part due to its involvement in the BMP/TGF-β signaling pathways. The Slc39a13-KO mouse represents a novel animal model linking zinc metabolism, BMP/TGF-β signaling and connective tissue dysfunction. PMID:18985159

The histidine transporter SLC15A4 coordinates mTOR-dependent inflammatory responses and pathogenic antibody production.

PubMed

Kobayashi, Toshihiko; Shimabukuro-Demoto, Shiho; Yoshida-Sugitani, Reiko; Furuyama-Tanaka, Kaori; Karyu, Hitomi; Sugiura, Yuki; Shimizu, Yukiko; Hosaka, Toshiaki; Goto, Motohito; Kato, Norihiro; Okamura, Tadashi; Suematsu, Makoto; Yokoyama, Shigeyuki; Toyama-Sorimachi, Noriko

2014-09-18

SLC15A4 is a lysosome-resident, proton-coupled amino-acid transporter that moves histidine and oligopeptides from inside the lysosome to the cytosol of eukaryotic cells. SLC15A4 is required for Toll-like receptor 7 (TLR7)- and TLR9-mediated type I interferon (IFN-I) productions in plasmacytoid dendritic cells (pDCs) and is involved in the pathogenesis of certain diseases including lupus-like autoimmunity. How SLC15A4 contributes to diseases is largely unknown. Here we have shown that B cell SLC15A4 was crucial for TLR7-triggered IFN-I and autoantibody productions in a mouse lupus model. SLC15A4 loss disturbed the endolysosomal pH regulation and probably the v-ATPase integrity, and these changes were associated with disruption of the mTOR pathway, leading to failure of the IFN regulatory factor 7 (IRF7)-IFN-I regulatory circuit. Importantly, SLC15A4's transporter activity was necessary for the TLR-triggered cytokine production. Our findings revealed that SLC15A4-mediated optimization of the endolysosomal state is integral to a TLR7-triggered, mTOR-dependent IRF7-IFN-I circuit that leads to autoantibody production. Copyright © 2014 Elsevier Inc. All rights reserved.

The ABCs of membrane transporters in health and disease (SLC series): Introduction☆☆☆

PubMed Central

Hediger, Matthias A.; Clémençon, Benjamin; Burrier, Robert E.; Bruford, Elspeth A.

2013-01-01

The field of transport biology has steadily grown over the past decade and is now recognized as playing an important role in manifestation and treatment of disease. The SLC (solute carrier) gene series has grown to now include 52 families and 395 transporter genes in the human genome. A list of these genes can be found at the HUGO Gene Nomenclature Committee (HGNC) website (see www.genenames.org/genefamilies/SLC). This special issue features mini-reviews for each of these SLC families written by the experts in each field. The existing online resource for solute carriers, the Bioparadigms SLC Tables (www.bioparadigms.org), has been updated and significantly extended with additional information and cross-links to other relevant databases, and the nomenclature used in this database has been validated and approved by the HGNC. In addition, the Bioparadigms SLC Tables functionality has been improved to allow easier access by the scientific community. This introduction includes: an overview of all known SLC and “non-SLC” transporter genes; a list of transporters of water soluble vitamins; a summary of recent progress in the structure determination of transporters (including GLUT1/SLC2A1); roles of transporters in human diseases and roles in drug approval and pharmaceutical perspectives. PMID:23506860

Boric acid increases the expression levels of human anion exchanger genes SLC4A2 and SLC4A3.

PubMed

Akbas, F; Aydin, Z

2012-04-03

Boron is an important micronutrient in plants and animals. The role of boron in living systems includes coordinated regulation of gene expression, growth and proliferation of higher plants and animals. There are several well-defined genes associated with boron transportation and tolerance in plants and these genes show close homology with human anion exchanger genes. Mutation of these genes also characterizes some genetic disorders. We investigated the toxic effects of boric acid on HEK293 cells and mRNA expression of anion exchanger (SLC4A1, SLC4A2 and SLC4A3) genes. Cytotoxicity of boric acid at different concentrations was tested by using the methylthiazolyldiphenyl-tetrazolium bromide assay. Gene expression profiles were examined using quantitative real-time PCR. In the HEK293 cells, the nontoxic upper concentration of boric acid was 250 μM; more than 500 μM caused cytotoxicity. The 250 μM boric acid concentration increased gene expression level of SLC4A2 up to 8.6-fold and SLC4A3 up to 2.6-fold, after 36-h incubation. There was no significant effect of boric acid on SLC4A1 mRNA expression levels.

SLC20A2 DEFICIENCY IN MICE LEADS TO ELEVATED PHOSPHATE LEVELS IN CEREBROSPINAL FLUID AND GLYMPHATIC PATHWAY-ASSOCIATED ARTERIOLAR CALCIFICATION, AND RECAPITULATES HUMAN IDIOPATHIC BASAL GANGLIA CALCIFICATION

PubMed Central

Wallingford, MC; Chia, J; Leaf, EM; Borgeia, S; Chavkin, NW; Sawangmake, C; Marro, K; Cox, TC; Speer, MY; Giachelli, CM

2016-01-01

Idiopathic basal ganglia calcification is a brain calcification disorder that has been genetically linked to autosomal dominant mutations in the sodium-dependent phosphate co-transporter, SLC20A2. The mechanisms whereby deficiency of Slc20a2 leads to basal ganglion calcification are unknown. In the mouse brain, we found that Slc20a2 was expressed in tissues that produce and/or regulate cerebrospinal fluid, including choroid plexus, ependyma and arteriolar smooth muscle cells. Haploinsufficient Slc20a2 +/− mice developed age-dependent basal ganglia calcification that formed in glymphatic pathway-associated arterioles. Slc20a2 deficiency uncovered phosphate homeostasis dysregulation characterized by abnormally high cerebrospinal fluid phosphate levels and hydrocephalus, in addition to basal ganglia calcification. Slc20a2 siRNA knockdown in smooth muscle cells revealed increased susceptibility to high phosphate-induced calcification. These data suggested that loss of Slc20a2 led to dysregulated phosphate homeostasis and enhanced susceptibility of arteriolar smooth muscle cells to elevated phosphate-induced calcification. Together, dysregulated cerebrospinal fluid phosphate and enhanced smooth muscle cell susceptibility may predispose to glymphatic pathway-associated arteriolar calcification. PMID:26822507

About cosmic gamma ray lines

NASA Astrophysics Data System (ADS)

Diehl, Roland

2017-06-01

Gamma ray lines from cosmic sources convey the action of nuclear reactions in cosmic sites and their impacts on astrophysical objects. Gamma rays at characteristic energies result from nuclear transitions following radioactive decays or high-energy collisions with excitation of nuclei. The gamma-ray line from the annihilation of positrons at 511 keV falls into the same energy window, although of different origin. We present here the concepts of cosmic gamma ray spectrometry and the corresponding instruments and missions, followed by a discussion of recent results and the challenges and open issues for the future. Among the lessons learned are the diffuse radioactive afterglow of massive-star nucleosynthesis in 26Al and 60Fe gamma rays, which is now being exploited towards the cycle of matter driven by massive stars and their supernovae; large interstellar cavities and superbubbles have been recognised to be of key importance here. Also, constraints on the complex processes making stars explode as either thermonuclear or core-collapse supernovae are being illuminated by gamma-ray lines, in this case from shortlived radioactivities from 56Ni and 44Ti decays. In particular, the three-dimensionality and asphericities that have recently been recognised as important are enlightened in different ways through such gamma-ray line spectroscopy. Finally, the distribution of positron annihilation gamma ray emission with its puzzling bulge-dominated intensity disctribution is measured through spatially-resolved spectra, which indicate that annihilation conditions may differ in different parts of our Galaxy. But it is now understood that a variety of sources may feed positrons into the interstellar medium, and their characteristics largely get lost during slowing down and propagation of positrons before annihilation; a recent microquasar flare was caught as an opportunity to see positrons annihilate at a source.

Extreme Hf-Os Isotope Compositions in Hawaiian Peridotite Xenoliths: Evidence for an Ancient Recycled Lithosphere

NASA Astrophysics Data System (ADS)

Bizimis, M.; Lassiter, J. C.; Salters, V. J.; Sen, G.; Griselin, M.

2004-12-01

We report on the first combined Hf-Os isotope systematics of spinel peridotite xenoliths from the Salt Lake Crater (SLC), Pali and Kaau (PK) vents from the island of Oahu, Hawaii. These peridotites are thought to represent the Pacific oceanic lithosphere beneath Oahu, as residues of MORB-type melting at a paleo-ridge some 80-100Ma ago. Clinopyroxene mineral separates in these peridotites have very similar Nd and Sr isotope compositions with the post erosional Honolulu Volcanics (HV) lavas that bring these xenoliths to the surface. This and their relatively elevated Na and LREE contents suggest that these peridotites are not simple residues of MORB-type melting but have experience some metasomatic enrichment by the host HV lavas. However, the SLC and PK xenoliths show an extreme range in Hf isotope compositions towards highly radiogenic values (ɛ Hf= 7-80), at nearly constant Nd isotope compositions (ɛ Nd= 7-10), unlike any OIB or MORB basalt. Furthermore, these Oahu peridotites show a bimodal distribution in their bulk rock 187Os/186Os ratios: the PK peridotites have similar ratios to the abyssal peridotites (0.130-0.1238), while the SLC peridotites have highly subchondritic ratios (0.1237-0.1134) that yield 500Ma to 2Ga Re-depletion ages. Hf-Os isotopes show a broad negative correlation whereby the samples with the most radiogenic 176Hf/177Hf have the most unradiogenic 187Os/186Os ratios. Based on their combined Hf-Os-Nd isotope and major element compositions, the PK peridotites can be interpreted as fragments of the Hawaiian lithosphere, residue of MORB melting 80-100Ma ago, that have been variably metasomatized by the host HV lavas. In contrast, the extreme Hf-Os isotope compositions of the SLC peridotites suggest that they cannot be the source nor residue of any kind of Hawaiian lavas, and that Hf and Os isotopes survived the metasomatism or melt-rock reaction that has overprinted the Nd and Sr isotope compositions of these peridotites. The ancient (>1Ga) melt depletion event recorded by both the low 187Os/186Os and high 176Hf/177Hf ratios in the SLC peridotites can be explained with two different scenarios. First, the SLC peridotites may represent ancient depleted lithosphere that survived subduction, remained "rafting" in the upper mantle and is now sampled beneath Oahu. However, the lack of such unradiogenic Os isotopes in both MORBs and abyssal peridotites suggests that such peridotites are rare in the upper mantle and makes their exclusive presence under Oahu a rather fortuitous coincidence. Alternatively, the SLC peridotites may represent ancient depleted recycled lithosphere brought up by the Hawaiian plume. A recycled oceanic crust origin has been previously invoked for the Koolau shield lavas. It is then conceivable that fragments of the lithospheric portion of that subducted package have remained coupled with the oceanic crust and are being brought up by the plume from the deep, but because they were previously depleted, these peridotites contribute minimally, if at all, to Hawaiian volcanism. The presence of microdiamonds and majoritic garnets in some SLC pyroxenites also corroborates a deep origin. In this case, the SLC peridotites represent the first-ever direct evidence that subducted material actually makes it back on the surface, essentially closing the subduction cycle.

Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer.

PubMed

Koppula, Pranavi; Zhang, Yilei; Zhuang, Li; Gan, Boyi

2018-04-25

Cancer cells often upregulate nutrient transporters to fulfill their increased biosynthetic and bioenergetic needs, and to maintain redox homeostasis. One nutrient transporter frequently overexpressed in human cancers is the cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11; also known as xCT). SLC7A11 promotes cystine uptake and glutathione biosynthesis, resulting in protection from oxidative stress and ferroptotic cell death. Recent studies have unexpectedly revealed that SLC7A11 also plays critical roles in glutamine metabolism and regulates the glucose and glutamine dependency of cancer cells. This review discusses the roles of SLC7A11 in regulating the antioxidant response and nutrient dependency of cancer cells, explores our current understanding of SLC7A11 regulation in cancer metabolism, and highlights key open questions for future studies in this emerging research area. A deeper understanding of SLC7A11 in cancer metabolism may identify new therapeutic opportunities to target this important amino acid transporter for cancer treatment.

New Baseline Design of the ILC RTML System

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seletskiy, S.; Kapin, V. V.; Solyak, N.

2012-05-01

The new ILC baseline was proposed in 2009 (Strawman baseline - SB2009) to minimize cost of the machine and accommodate many changes made in the design of the accelerator systems. The biggest changes are made in the central area, where BDS, RTM L, DR, electron and positron sources are sharing the tunnels. A new layout of the compact DR and re-location of the electron and positron sources to the main tunnel requires a new lattice design for all beamlines in this area. The lattice design was coord inated between accelerator systems and Convention Facility and Siting (CFS) group to eliminatemore » conflicts between beamlines and satisfy construction requirements. In this paper we present a new design of the RTML electron and positron lattices in the centr al area and other modifications made in the RTML line to accommodate changes to the beamline layouts.« less

High-intensity positron microprobe at Jefferson Lab

DOE PAGES

Golge, Serkan; Vlahovic, Branislav; Wojtsekhowski, Bogdan B.

2014-06-19

We present a conceptual design for a novel continuous wave electron-linac based high-intensity slow-positron production source with a projected intensity on the order of 10 10 e +/s. Reaching this intensity in our design relies on the transport of positrons (T + below 600 keV) from the electron-positron pair production converter target to a low-radiation and low-temperature area for moderation in a high-efficiency cryogenic rare gas moderator, solid Ne. The performance of the integrated beamline has been verified through computational studies. The computational results include Monte Carlo calculations of the optimized electron/positron beam energies, converter target thickness, synchronized raster system,more » transport of the beam from the converter target to the moderator, extraction of the beam from the channel, and moderation efficiency calculations. For the extraction of positrons from the magnetic channel a magnetic field terminator plug prototype has been built and experimental data on the effectiveness of this prototype are presented. The dissipation of the heat away from the converter target and radiation protection measures are also discussed.« less

The Factor Structure and Sources of Variation Underlying the Social Learning Environment Rating Scales: Monograph 1.

ERIC Educational Resources Information Center

Warshow, Joyce P.; Bepko, Raymond A.

Seventeen intermediate level classes for the educable mentally retarded were involved in an investigation of the factor structure of the Social Learning Environment Rating Scale (SLERS), an instrument designed to quantify teacher-student behavior based on the Social Learning Curriculum (SLC). The 17 classes were observed implementing six…

Asymmetric 511 keV Positron Annihilation Line Emission from the Inner Galactic Disk

NASA Technical Reports Server (NTRS)

Skinner, Gerry; Weidenspointner, Georg; Jean, Pierre; Knodlseder, Jurgen; Ballmoos, Perer von; Bignami, Giovanni; Diehl, Roland; Strong, Andrew; Cordier, Bertrand; Schanne, Stephane;

Pathogenic substitution of IVS15 + 5G > A in SLC26A4 in patients of Okinawa Islands with enlarged vestibular aqueduct syndrome or Pendred syndrome.

PubMed

Ganaha, Akira; Kaname, Tadashi; Yanagi, Kumiko; Naritomi, Kenji; Tono, Tetsuya; Usami, Shin-ichi; Suzuki, Mikio

2013-05-24

Pendred syndrome (PS) and nonsyndromic hearing loss associated with enlarged vestibular aqueduct (EVA) are caused by SLC26A4 mutations. The Okinawa Islands are the southwestern-most islands of the Japanese archipelago. And ancestral differences have been reported between people from Okinawa Island and those from the main islands of Japan. To confirm the ethnic variation of the spectrum of SLC26A4 mutations, we investigated the frequencies of SLC26A4 mutations and clinical manifestations of patients with EVA or PS living in the Okinawa Islands. We examined 22 patients with EVA or PS from 21 unrelated families in Okinawa Islands. The patient's clinical history, findings of physical and otoscopic examinations, hearing test, and computed tomography (CT) scan of the temporal bones were recorded. To detect mutations, all 21 exons and the exon-intron junctions of SLC26A4 were sequenced for all subjects. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) for SLC26A4 and calculations using the comparative CT (2(-ΔΔCT)) method were used to determine the pathogenicity associated with gene substitutions. SLC26A4 mutations were identified in 21 of the 22 patients. We found a compound heterozygous mutation for IVS15 + 5G > A/H723R in nine patients (41%), a homozygous substitution of IVS15 + 5G > A in six patients (27%), and homozygous mutation for H723R in five patients (23%). The most prevalent types of SLC26A4 alleles were IVS15 + 5G > A and H723R, which both accounted for 15/22 (68%) of the patients. There were no significant correlations between the types of SLC26A4 mutation and clinical manifestations. Based on qRT-PCR results, expression of SLC26A4 was not identified in patients with the homozygous substitution of IVS15 + 5G > A. The substitution of IVS15 + 5G > A in SLC26A4 was the most common mutation in uniquely found in patients with PS and EVA in Okinawa Islands. This suggested that the spectrum of SLC26A4 mutation differed from main islands of Japan and other East Asian countries. The substitution of IVS15 + 5G > A leads to a loss of SLC26A expression and results in a phenotype of PS and EVA.

Pathogenic substitution of IVS15 + 5G > A in SLC26A4 in patients of Okinawa Islands with enlarged vestibular aqueduct syndrome or Pendred syndrome

PubMed Central

2013-01-01

Background Pendred syndrome (PS) and nonsyndromic hearing loss associated with enlarged vestibular aqueduct (EVA) are caused by SLC26A4 mutations. The Okinawa Islands are the southwestern-most islands of the Japanese archipelago. And ancestral differences have been reported between people from Okinawa Island and those from the main islands of Japan. To confirm the ethnic variation of the spectrum of SLC26A4 mutations, we investigated the frequencies of SLC26A4 mutations and clinical manifestations of patients with EVA or PS living in the Okinawa Islands. Methods We examined 22 patients with EVA or PS from 21 unrelated families in Okinawa Islands. The patient’s clinical history, findings of physical and otoscopic examinations, hearing test, and computed tomography (CT) scan of the temporal bones were recorded. To detect mutations, all 21 exons and the exon–intron junctions of SLC26A4 were sequenced for all subjects. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) for SLC26A4 and calculations using the comparative CT (2−ΔΔCT) method were used to determine the pathogenicity associated with gene substitutions. Results SLC26A4 mutations were identified in 21 of the 22 patients. We found a compound heterozygous mutation for IVS15 + 5G > A/H723R in nine patients (41%), a homozygous substitution of IVS15 + 5G > A in six patients (27%), and homozygous mutation for H723R in five patients (23%). The most prevalent types of SLC26A4 alleles were IVS15 + 5G > A and H723R, which both accounted for 15/22 (68%) of the patients. There were no significant correlations between the types of SLC26A4 mutation and clinical manifestations. Based on qRT-PCR results, expression of SLC26A4 was not identified in patients with the homozygous substitution of IVS15 + 5G > A. Conclusions The substitution of IVS15 + 5G > A in SLC26A4 was the most common mutation in uniquely found in patients with PS and EVA in Okinawa Islands. This suggested that the spectrum of SLC26A4 mutation differed from main islands of Japan and other East Asian countries. The substitution of IVS15 + 5G > A leads to a loss of SLC26A expression and results in a phenotype of PS and EVA. PMID:23705809

Solute carrier transporters: potential targets for digestive system neoplasms.

PubMed

Xie, Jing; Zhu, Xiao Yan; Liu, Lu Ming; Meng, Zhi Qiang

2018-01-01

Digestive system neoplasms are the leading causes of cancer-related death all over the world. Solute carrier (SLC) superfamily is composed of a series of transporters that are ubiquitously expressed in organs and tissues of digestive systems and mediate specific uptake of small molecule substrates in facilitative manner. Given the important role of SLC proteins in maintaining normal functions of digestive system, dysregulation of these protein in digestive system neoplasms may deliver biological and clinical significance that deserves systemic studies. In this review, we critically summarized the recent advances in understanding the role of SLC proteins in digestive system neoplasms. We highlighted that several SLC subfamilies, including metal ion transporters, transporters of glucose and other sugars, transporters of urea, neurotransmitters and biogenic amines, ammonium and choline, inorganic cation/anion transporters, transporters of nucleotide, amino acid and oligopeptide organic anion transporters, transporters of vitamins and cofactors and mitochondrial carrier, may play important roles in mediating the initiation, progression, metastasis, and chemoresistance of digestive system neoplasms. Proteins in these SLC subfamilies may also have diagnostic and prognostic values to particular cancer types. Differential expression of SLC proteins in tumors of digestive system was analyzed by extracting data from human cancer database, which revealed that the roles of SLC proteins may either be dependent on the substrates they transport or be tissue specific. In addition, small molecule modulators that pharmacologically regulate the functions of SLC proteins were discussed for their possible application in the treatment of digestive system neoplasms. This review highlighted the potential of SLC family proteins as drug target for the treatment of digestive system neoplasms.

Solute carrier transporters: potential targets for digestive system neoplasms

PubMed Central

Xie, Jing; Zhu, Xiao Yan; Liu, Lu Ming; Meng, Zhi Qiang

2018-01-01

Digestive system neoplasms are the leading causes of cancer-related death all over the world. Solute carrier (SLC) superfamily is composed of a series of transporters that are ubiquitously expressed in organs and tissues of digestive systems and mediate specific uptake of small molecule substrates in facilitative manner. Given the important role of SLC proteins in maintaining normal functions of digestive system, dysregulation of these protein in digestive system neoplasms may deliver biological and clinical significance that deserves systemic studies. In this review, we critically summarized the recent advances in understanding the role of SLC proteins in digestive system neoplasms. We highlighted that several SLC subfamilies, including metal ion transporters, transporters of glucose and other sugars, transporters of urea, neurotransmitters and biogenic amines, ammonium and choline, inorganic cation/anion transporters, transporters of nucleotide, amino acid and oligopeptide organic anion transporters, transporters of vitamins and cofactors and mitochondrial carrier, may play important roles in mediating the initiation, progression, metastasis, and chemoresistance of digestive system neoplasms. Proteins in these SLC subfamilies may also have diagnostic and prognostic values to particular cancer types. Differential expression of SLC proteins in tumors of digestive system was analyzed by extracting data from human cancer database, which revealed that the roles of SLC proteins may either be dependent on the substrates they transport or be tissue specific. In addition, small molecule modulators that pharmacologically regulate the functions of SLC proteins were discussed for their possible application in the treatment of digestive system neoplasms. This review highlighted the potential of SLC family proteins as drug target for the treatment of digestive system neoplasms. PMID:29416375

Satellite Observations of Annihilation of Positrons Produced at the Sun, the Earth, and Center of our Galaxy

NASA Astrophysics Data System (ADS)

Share, G. H.; Murphy, R. J.; Lin, R. P.

2007-05-01

Positrons are created in nuclear interactions that produce β +-unstable nuclei and pi+ mesons. Satellites remotely observe positron production when they annihilate with electrons yielding the characteristic line at 511 keV. Radiation detectors such as the germanium diodes on the Ramaty High-Energy Solar Spectrocopic Imager (RHESSI) observe this line from positrons by nuclei activated in the spacecraft by proton interactions during transit through the Earth's radiation belts and from cosmic radiation. This forms an intense background for solar and astrophysical observations. RHESSI and other satellites have observed positron annihilation in over 50 solar flares. These measurements provide information on the temperature, density, and ionization state of solar atmosphere where the positrons annihilate. The measurements suggest that up to a few kg of positrons are produced in these flares. Detectable annihilation-line radiation is also emitted from the Earth's atmosphere in interactions of cosmic rays and solar energetic particles. An extended annihilation-line source has also been detected within about 10 degrees of the center of the Milky Way that is attributed to positrons released in radioactive decays of nuclei with long half-lives produced in supernovae, novae, and other stellar explosions. From 1980 to 1988 NASA's Solar Maximum Mission satellite also detected belts of positrons emitted by nuclear reactors onboard KOSMOS satellites and trapped temporarily in the Earth's magnetic field. This work was supported by NASA Supporting Research & Technology grants.

Case-control approach application for finding a relationship between candidate genes and clinical mastitis in Holstein dairy cattle.

PubMed

Bagheri, Masoumeh; Moradi-Sharhrbabak, M; Miraie-Ashtiani, R; Safdari-Shahroudi, M; Abdollahi-Arpanahi, R

2016-02-01

Mastitis is a major source of economic loss in dairy herds. The objective of this research was to evaluate the association between genotypes within SLC11A1 and CXCR1 candidate genes and clinical mastitis in Holstein dairy cattle using the selective genotyping method. The data set contained clinical mastitis records of 3,823 Holstein cows from two Holstein dairy herds located in two different regions in Iran. Data included the number of cases of clinical mastitis per lactation. Selective genotyping was based on extreme values for clinical mastitis residuals (CMR) from mixed model analyses. Two extreme groups consisting of 135 cows were formed (as cases and controls), and genotyped for the two candidate genes, namely, SLC11A1 and CXCR1, using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), respectively. Associations between single nucleotide polymorphism (SNP) genotypes with CMR and breeding values for milk and protein yield were carried out by applying logistic regression analyses, i.e. estimating the probability of the heterogeneous genotype in the dependency of values for CMR and breeding values (BVs). The sequencing results revealed a novel mutation in 1139 bp of exon 11 of the SLC11A1 gene and this SNP had a significant association with CMR (P < 0.05). PCR-RFLP analysis leads to three banding patterns for CXCR1c.735C>G and these genotypes had significant relationships with CMR. Overall, the results showed that SLC11A1 and CXCR1 are valuable candidate genes for the improvement of mastitis resistance as well as production traits in dairy cattle populations.

Evaluating the purity of a {sup 57}Co flood source by PET

DOE Office of Scientific and Technical Information (OSTI.GOV)

DiFilippo, Frank P., E-mail: difilif@ccf.org

2014-11-01

Purpose: Flood sources of {sup 57}Co are commonly used for quality control of gamma cameras. Flood uniformity may be affected by the contaminants {sup 56}Co and {sup 58}Co, which emit higher energy photons. Although vendors specify a maximum combined {sup 56}Co and {sup 58}Co activity, a convenient test for flood source purity that is feasible in a clinical environment would be desirable. Methods: Both {sup 56}Co and {sup 58}Co emit positrons with branching 19.6% and 14.9%, respectively. As is known from {sup 90}Y imaging, a positron emission tomography (PET) scanner is capable of quantitatively imaging very weak positron emission inmore » a high single-photon background. To evaluate this approach, two {sup 57}Co flood sources were scanned with a clinical PET/CT multiple times over a period of months. The {sup 56}Co and {sup 58}Co activity was clearly visible in the reconstructed PET images. Total impurity activity was quantified from the PET images after background subtraction of prompt gamma coincidences. Results: Time-of-flight PET reconstruction was highly beneficial for accurate image quantification. Repeated measurements of the positron-emitting impurities showed excellent agreement with an exponential decay model. For both flood sources studied, the fit parameters indicated a zero intercept and a decay half-life consistent with a mixture of {sup 56}Co and {sup 58}Co. The total impurity activity at the reference date was estimated to be 0.06% and 0.07% for the two sources, which was consistent with the vendor’s specification of <0.12%. Conclusions: The robustness of the repeated measurements and a thorough analysis of the detector corrections and physics suggest that the accuracy is acceptable and that the technique is feasible. Further work is needed to validate the accuracy of this technique with a calibrated high resolution gamma spectrometer as a gold standard, which was not available for this study, and for other PET detector models.« less

2. GENERAL VIEW OF SLC3 AIR FORCE BUILDING (BLDG. 761) ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

2. GENERAL VIEW OF SLC-3 AIR FORCE BUILDING (BLDG. 761) FROM THE NORTHWEST - Vandenberg Air Force Base, Space Launch Complex 3, SLC-3 Air Force Building, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

1. GENERAL VIEW OF SLC3 AIR FORCE BUILDING (BLDG. 761) ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

1. GENERAL VIEW OF SLC-3 AIR FORCE BUILDING (BLDG. 761) FROM THE SOUTHWEST - Vandenberg Air Force Base, Space Launch Complex 3, SLC-3 Air Force Building, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

Tertiary particle physics with ELI: from challenge to chance (Conference Presentation)

NASA Astrophysics Data System (ADS)

Drska, Ladislav

2017-05-01

nteraction of high-intensity laser pulses with solid state targets results in generation of intense pulses of secondary particles via electromagnetic interaction : electrons, ions, hard x-rays. The beams of these particles can be used to produce various types of third-generation particles, beyond electromagnetic also other types of fundamental interactions can be involved in this process [1]. As the most interesting tertiary particles could be mentioned positrons, neutron, muons. This paper shall extend our previous analysis of this topic [2]: it discusses selected technical problems of design and realization of applicable sources of these particles and presents some more elaborated proposals for potential meaningful / hopefuly realistic exploitations of this technology. (1)Tertiary Sources (TS) : First Development Steps. This part of the presentation includes the topics as follows: (11) Pulsed positron sources: Verified solutions of laser-driven positron sources [3] [4] [5], development towards applicable facilities. Some unconventional concepts of application of lasers for positron production [6]. Techniques for realization of low/very-low energy positrons. (12) Taylored neutron sources [7]: Neutron sources with demanded space distribution, strongly beamed and isotropic solutions [8] [9]. Neutron generation with taylored energy distribution. Problem of the direct production of neutrons with very low energy [10] [11]. (13) Potential muon sources: Proof-of-principle laser experiment on electron / photon driven muon production [12] [13]. Study of the possibility of effective generation of surface muons. Problems of the production of muons with very low energy. (2) Fundamental & Applied Physics with TS: This part of the talk presents the themes: (21) Diagnostic potential of TS: Lepton emission as a signature of processes in extreme systems. Passive and active diagnostics using positrons, problems of detection and evaluation. Potential diagnostic applications of muons. Concrete application study: muon tomography. (22) Antilepton gravity studies [14]: Possibility of antimattter gravity research using positronium and muonium [15] [16]. Lepton / antilepton gravity studiesactive with relativistic particle beams [17]. First-phase practical application : positron production for filling (commertial) particle traps, development base for multiple microtrap systems. (23) Hidden world searching [18] : Potential laser-based production / detection of selected dark mattter particles - axions, hidden photons [19] [20]. Search for hidden particles in nuclear decay processes [21]. Potential application output: intense positronium source. Conclusion: The extensive feasibility study confirms the potential of ELI to contribute to the solution of Grand Challenge Problems of physics. Laser-produced tertiary particles will play important role in this effort. : References [1] L.Drska et al.: Physics of Extreme Systems. Course ATHENS CTU18, Prague 12 - 19 Nov., 2016. http://vega.fjfi.cvut.cz/docs/athens2016/ [2] L.Drska : Lepton Diagnostics and Antimatter Physics. In: SPIE Optics+Optoelectronics, Prague, April 13 - 16, 2015 . [3] H. Chen et al.: Scaling the Yield of Laser-Driven Electron-Positron Jets to Laboratory Astrophysics Applications. Rep. LLNL-JRNL-665381, Dec. 11, 2014. [4] E Liang et al.: High e+ / e- Ratio Dense Pair Creation with 1022 W.cm-2 Laser Irradiating Solid Targets. Scientific Reports, Sept. 14, 2015. www.nature.com/scientificreports [5] G. Sarri et al.: Spectral and Spatial Characterization of Laser-driven Positron Beams. Plasma Phys. Control. Fusion 59 (2017) 014015. [6] B. Schoch: A Method to Produce Intense Positron Beams via Electro Pair Production on Electrons. arXiv:1607.03847v1 [physics.acc-ph] [7] I. Pomerantz: Laser Generation of Neutrons: Science and Applications. In: ELI-NP Summer School, Magurele, Sept. 21 - 25, 2015. http://www.eli-np.ro/2015-summer-school/presentations/23.09/Pomerantz_Eli-NP-Summer-school-2015.pdf [8] V.P. Kovalev: Secondary Radiation of Electron Accelerators (in Russian). Atomizdat 1969. [9] M. Lebois et al.: Development of a Kinematically Focused Neutron Source with p(Li7,n)Be7 Inverse Reaction. Nucl. Instr. Meth. Phys. Res. A 735 (2014), 145. [10] D. Habs et al.: Neutron Halo Isomers in Stable Nuclei and their Possible Application for the Production of Low Energy, Pulsed, Polarized Neutron Beams of High Intensity and High Brilliance. Appl. Phys B103 (2011),485. [11] T. Masuda et al.: A New Method of Creating High/Intensity Neutron Source. arXiv:1604.02818v1[nucl-ex] [12] A.I. Titov et al.: Dimuon Production by Laser-wakefield Accelerated Electrons. Phys. Rev. ST Accel. Beams 12 (2009) 111301. [13] W. Dreesen et al.: Detection of Petawatt Laser-Induced Muon Source for Rapid High-Gamma Material Detection. DOE/NV/25946-2262. [14] F. Castelli: Positronium and Fundamental Physics: What Next ? In: What Next, Florence 2015. [15] G. Dufour et al. : Prospects for Studies of the Free Fall and Gravitation Quantum States of Antimatter. Advances in High Energy Physics 2015 (2015) 379642. [16] D.M. Kaplan et al.. Antimatter Gravity with Muonium. IIT-CAPP-16-1. arXiv:1601.07222v2 [physics.ins-det] [17] T. Kalaydzhyan: Gravitational Mass of Positron from LEP Synchrotron Losses. arXiv:1508.04377v3 [hep-ph] [18] J. Alexander et al.: Dark Sector 2016 Workshop: Community Report. arXiv:1608.08632[hep-ph] [19] M.A. Wahud et al.: Axion-like Particle Production in a Laser-Induced Dynamical Spacertime. arXiv:1612.07743v1 [hep-ph] [20] V. Kozhuharov et al: New Projects on Dark Photon Search. arXiv:1610.04389v1 [hep-ex] [21] A.J. Krasznahorkay et al.: Observation of Anomalous Internal Pair Creation in Be8: A Possible Signature of a Light, Neutral Boson. arXiv:1504.01527v1 [nucl-ex

Additive composite ABCG2, SLC2A9 and SLC22A12 scores of high-risk alleles with alcohol use modulate gout risk.

PubMed

Tu, Hung-Pin; Chung, Chia-Min; Min-Shan Ko, Albert; Lee, Su-Shin; Lai, Han-Ming; Lee, Chien-Hung; Huang, Chung-Ming; Liu, Chiu-Shong; Ko, Ying-Chin

2016-09-01

The aim of the present study was to evaluate the contribution of urate transporter genes and alcohol use to the risk of gout/tophi. Eight variants of ABCG2, SLC2A9, SLC22A12, SLC22A11 and SLC17A3 were genotyped in male individuals in a case-control study with 157 gout (33% tophi), 106 asymptomatic hyperuricaemia and 295 control subjects from Taiwan. The multilocus profiles of the genetic risk scores for urate gene variants were used to evaluate the risk of asymptomatic hyperuricaemia, gout and tophi. ABCG2 Q141K (T), SLC2A9 rs1014290 (A) and SLC22A12 rs475688 (C) under an additive model and alcohol use independently predicted the risk of gout (respective odds ratio for each factor=2.48, 2.03, 1.95 and 2.48). The additive composite Q141K, rs1014290 and rs475688 scores of high-risk alleles were associated with gout risk (P<0.0001). We observed the supramultiplicative interaction effect of genetic urate scores and alcohol use on gout and tophi risk (P for interaction=0.0452, 0.0033). The synergistic effect of genetic urate score 5-6 and alcohol use indicates that these combined factors correlate with gout and tophi occurrence.

Identification and functional characterization of a solute carrier family 15, member 4 gene in Litopenaeus vannamei.

PubMed

Chen, Yong-Gui; Yuan, Kai; Zhang, Ze-Zhi; Yuan, Feng-Hua; Weng, Shao-Ping; Yue, Hai-Tao; He, Jian-Guo; Chen, Yi-Hong

2016-04-01

Innate immunity in shrimp is important in resisting bacterial infection. The NF-κB pathway is pivotal in such an immune response. This study cloned and functionally characterized the solute carrier family (SLC) 15 member A 4 (LvSLC15A4) gene in Litopenaeus vannamei. The open reading frame of LvSLC15A4 is 1, 902 bp long and encodes a putative 633-amino acid protein, which is localized in the plasma membrane and intracellular vesicular compartments. Results of the reporter gene assay showed that LvSLC15A4 upregulated NF-κB target genes, including the immediate-early gene 1 of white spot syndrome virus, as well as several antimicrobial peptide genes, such as pen4, CecA, AttA, and Mtk in S2 cells. Moreover, knocked-down expression of LvSLC15A4 reduced pen4 expression in L. vannamei. LvSLC15A4 down-regulation also increased the cumulative mortality of Vibrio parahemolyticus-infected L. vannamei. Furthermore, LvSLC15A4 expression was induced by unfolded protein response (UPR) in L. vannamei hematocytes. These results suggest that LvSLC15A4 participates in L. vannamei innate immunity via the NF-κB pathway and thus may be related to UPR. Copyright © 2015 Elsevier Ltd. All rights reserved.

Functional Characterization of 5-Oxoproline Transport via SLC16A1/MCT1*

PubMed Central

Sasaki, Shotaro; Futagi, Yuya; Kobayashi, Masaki; Ogura, Jiro; Iseki, Ken

2015-01-01

Thyrotropin-releasing hormone is a tripeptide that consists of 5-oxoproline, histidine, and proline. The peptide is rapidly metabolized by various enzymes. 5-Oxoproline is produced by enzymatic hydrolysis in a variety of peptides. Previous studies showed that 5-oxoproline could become a possible biomarker for autism spectrum disorders. Here we demonstrate the involvement of SLC16A1 in the transport of 5-oxoproline. An SLC16A1 polymorphism (rs1049434) was recently identified. However, there is no information about the effect of the polymorphism on SLC16A1 function. In this study, the polymorphism caused an observable change in 5-oxoproline and lactate transport via SLC16A1. The Michaelis constant (Km) was increased in an SLC16A1 mutant compared with that in the wild type. In addition, the proton concentration required to produce half-maximal activation of transport activity (K0.5, H+) was increased in the SLC16A1 mutant compared with that in the wild type. Furthermore, we examined the transport of 5-oxoproline in T98G cells as an astrocyte cell model. Despite the fact that 5-oxoproline is an amino acid derivative, Na+-dependent and amino acid transport systems scarcely contributed to 5-oxoproline transport. Based on our findings, we conclude that H+-coupled 5-oxoproline transport is mediated solely by SLC16A1 in the cells. PMID:25371203

Activation of lysosomal P2X4 by ATP transported into lysosomes via VNUT/SLC17A9 using V‐ATPase generated voltage gradient as the driving force

PubMed Central

Zhong, Xi Zoë; Cao, Qi; Sun, Xue

2016-01-01

Key points SLC17A9 proteins function as a lysosomal ATP transporter responsible for lysosomal ATP accumulation.P2X4 receptors act as lysosomal ion channels activated by luminal ATP.SLC17A9‐mediated ATP transport across the lysosomal membrane is suppressed by Bafilomycin A1, the V‐ATPase inhibitor.SLC17A9 mainly uses voltage gradient but not pH gradient generated by the V‐ATPase as the driving force to transport ATP into the lysosome to activate P2X4. Abstract The lysosome contains abundant ATP which plays important roles in lysosome functions and in cell signalling. Recently, solute carrier family 17 member 9 (SLC17A9, also known as VNUT for vesicular nucleotide transporter) proteins were suggested to function as a lysosomal ATP transporter responsible for lysosomal ATP accumulation, and P2X4 receptors were suggested to be lysosomal ion channels that are activated by luminal ATP. However, the molecular mechanism of SLC17A9 transporting ATP and the regulatory mechanism of lysosomal P2X4 are largely unknown. In this study, we report that SLC17A9‐mediated ATP transport across lysosomal membranes is suppressed by Bafilomycin A1, the V‐ATPase inhibitor. By measuring P2X4 activity, which is indicative of ATP transport across lysosomal membranes, we further demonstrated that SLC17A9 mainly uses voltage gradient but not pH gradient as the driving force to transport ATP into lysosomes. This study provides a molecular mechanism for lysosomal ATP transport mediated by SLC17A9. It also suggests a regulatory mechanism of lysosomal P2X4 by SLC17A9. PMID:27477609

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gabrielson, Marike; Reizer, Edwin; Stål, Olle

An increasing body of evidence is pointing towards mitochondrial regulation of the cell cycle. In a previous study of HER2-positive tumours we could demonstrate a common loss in the gene encoding for the mitochondrial transporter SLC25A43 and also a significant relation between SLC25A43 protein expression and S-phase fraction. Here, we investigated the consequence of suppressed SLC25A43 expression on cell cycle progression and proliferation in breast epithelial cells. In the present study, we suppressed SLC25A43 using siRNA in immortalised non-cancerous breast epithelial MCF10A cells and HER2-positive breast cancer cells BT-474. Viability, apoptosis, cell proliferation rate, cell cycle phase distribution, and nuclearmore » Ki-67 and p21, were assessed by flow cytometry. Cell cycle related gene expressions were analysed using real-time PCR. We found that SLC25A43 knockdown in MCF10A cells significantly inhibited cell cycle progression during G{sub 1}-to-S transition, thus significantly reducing the proliferation rate and fraction of Ki-67 positive MCF10A cells. In contrast, suppressed SLC25A43 expression in BT-474 cells resulted in a significantly increased proliferation rate together with an enhanced G{sub 1}-to-S transition. This was reflected by an increased fraction of Ki-67 positive cells and reduced level of nuclear p21. In line with our previous results, we show a role for SLC25A43 as a regulator of cell cycle progression and proliferation through a putative mitochondrial checkpoint. These novel data further strengthen the connection between mitochondrial function and the cell cycle, both in non-malignant and in cancer cells. - Highlights: • Proposed cell cycle regulation through the mitochondrial transporter SLC25A43. • SLC25A43 alters cell proliferation rate and cell cycle progression. • Suppressed SLC25A43 influences transcription of cell cycle regulatory genes.« less

SLC26A4 mutation testing for hearing loss associated with enlargement of the vestibular aqueduct

PubMed Central

Ito, Taku; Muskett, Julie; Chattaraj, Parna; Choi, Byung Yoon; Lee, Kyu Yup; Zalewski, Christopher K; King, Kelly A; Li, Xiangming; Wangemann, Philine; Shawker, Thomas; Brewer, Carmen C; Alper, Seth L; Griffith, Andrew J

2014-01-01

Pendred syndrome (PS) is characterized by autosomal recessive inheritance of goiter associated with a defect of iodide organification, hearing loss, enlargement of the vestibular aqueduct (EVA), and mutations of the SLC26A4 gene. However, not all EVA patients have PS or SLC26A4 mutations. Two mutant alleles of SLC26A4 are detected in ¼ of North American or European EVA populations, one mutant allele is detected in another ¼ of patient populations, and no mutations are detected in the other ½. The presence of two mutant alleles of SLC26A4 is associated with abnormal iodide organification, increased thyroid gland volume, increased severity of hearing loss, and bilateral EVA. The presence of a single mutant allele of SLC26A4 is associated with normal iodide organification, normal thyroid gland volume, less severe hearing loss and either bilateral or unilateral EVA. When other underlying correlations are accounted for, the presence of a cochlear malformation or the size of EVA does not have an effect on hearing thresholds. This is consistent with observations of an Slc26a4 mutant mouse model of EVA in which hearing loss is independent of endolymphatic hydrops or inner ear malformations. Segregation analyses of EVA in families suggest that the patients carrying one mutant allele of SLC26A4 have a second, undetected mutant allele of SLC26A4, and the probability of a sibling having EVA is consistent with its segregation as an autosomal recessive trait. Patients without any mutations are an etiologically heterogeneous group in which siblings have a lower probability of having EVA. SLC26A4 mutation testing can provide prognostic information to guide clinical surveillance and management, as well as the probability of EVA affecting a sibling. PMID:25960948

Sodium-coupled electrogenic transport of pyroglutamate (5-oxoproline) via SLC5A8, a monocarboxylate transporter.

PubMed

Miyauchi, Seiji; Gopal, Elangovan; Babu, Ellappan; Srinivas, Sonne R; Kubo, Yoshiyuki; Umapathy, Nagavedi S; Thakkar, Santoshanand V; Ganapathy, Vadivel; Prasad, Puttur D

2010-06-01

Pyroglutamate, also known as 5-oxoproline, is a structural analog of proline. This amino acid derivative is a byproduct of glutathione metabolism, and is reabsorbed efficiently in kidney by Na(+)-coupled transport mechanisms. Previous studies have focused on potential participation of amino acid transport systems in renal reabsorption of this compound. Here we show that it is not the amino acid transport systems but instead the Na(+)-coupled monocarboxylate transporter SLC5A8 that plays a predominant role in this reabsorptive process. Expression of cloned human and mouse SLC5A8 in mammalian cells induces Na(+)-dependent transport of pyroglutamate that is inhibitable by various SLC5A8 substrates. SLC5A8-mediated transport of pyroglutamate is saturable with a Michaelis constant of 0.36+/-0.04mM. Na(+)-activation of the transport process exhibits sigmoidal kinetics with a Hill coefficient of 1.8+/-0.4, indicating involvement of more than one Na(+) in the activation process. Expression of SLC5A8 in Xenopuslaevis oocytes induces Na(+)-dependent inward currents in the presence of pyroglutamate under voltage-clamp conditions. The concentration of pyroglutamate necessary for induction of half-maximal current is 0.19+/-0.01mM. The Na(+)-activation kinetics is sigmoidal with a Hill coefficient of 2.3+/-0.2. Ibuprofen, a blocker of SLC5A8, suppressed pyroglutamate-induced currents in SLC5A8-expressing oocytes; the concentration of the blocker necessary for causing half-maximal inhibition is 14+/-1microM. The involvement of SLC5A8 can be demonstrated in rabbit renal brush border membrane vesicles by showing that the Na(+)-dependent uptake of pyroglutamate in these vesicles is inhibitable by known substrates of SLC5A8. The Na(+) gradient-driven pyroglutamate uptake was stimulated by an inside-negative K(+) diffusion potential induced by valinomycin, showing that the uptake process is electrogenic.

Evaluation of scatter limitation correction: a new method of correcting photopenic artifacts caused by patient motion during whole-body PET/CT imaging.

PubMed

Miwa, Kenta; Umeda, Takuro; Murata, Taisuke; Wagatsuma, Kei; Miyaji, Noriaki; Terauchi, Takashi; Koizumi, Mitsuru; Sasaki, Masayuki

2016-02-01

Overcorrection of scatter caused by patient motion during whole-body PET/computed tomography (CT) imaging can induce the appearance of photopenic artifacts in the PET images. The present study aimed to quantify the accuracy of scatter limitation correction (SLC) for eliminating photopenic artifacts. This study analyzed photopenic artifacts in (18)F-fluorodeoxyglucose ((18)F-FDG) PET/CT images acquired from 12 patients and from a National Electrical Manufacturers Association phantom with two peripheral plastic bottles that simulated the human body and arms, respectively. The phantom comprised a sphere (diameter, 10 or 37 mm) containing fluorine-18 solutions with target-to-background ratios of 2, 4, and 8. The plastic bottles were moved 10 cm posteriorly between CT and PET acquisitions. All PET data were reconstructed using model-based scatter correction (SC), no scatter correction (NSC), and SLC, and the presence or absence of artifacts on the PET images was visually evaluated. The SC and SLC images were also semiquantitatively evaluated using standardized uptake values (SUVs). Photopenic artifacts were not recognizable in any NSC and SLC image from all 12 patients in the clinical study. The SUVmax of mismatched SLC PET/CT images were almost equal to those of matched SC and SLC PET/CT images. Applying NSC and SLC substantially eliminated the photopenic artifacts on SC PET images in the phantom study. SLC improved the activity concentration of the sphere for all target-to-background ratios. The highest %errors of the 10 and 37-mm spheres were 93.3 and 58.3%, respectively, for mismatched SC, and 73.2 and 22.0%, respectively, for mismatched SLC. Photopenic artifacts caused by SC error induced by CT and PET image misalignment were corrected using SLC, indicating that this method is useful and practical for clinical qualitative and quantitative PET/CT assessment.

A novel sodium bicarbonate cotransporter-like gene in an ancient duplicated region: SLC4A9 at 5q31

PubMed Central

Lipovich, Leonard; Lynch, Eric D; Lee, Ming K; King, Mary-Claire

2001-01-01

Background: Sodium bicarbonate cotransporter (NBC) genes encode proteins that execute coupled Na+ and HCO3- transport across epithelial cell membranes. We report the discovery, characterization, and genomic context of a novel human NBC-like gene, SLC4A9, on chromosome 5q31. Results: SLC4A9 was initially discovered by genomic sequence annotation and further characterized by sequencing of long-insert cDNA library clones. The predicted protein of 990 amino acids has 12 transmembrane domains and high sequence similarity to other NBCs. The 23-exon gene has 14 known mRNA isoforms. In three regions, mRNA sequence variation is generated by the inclusion or exclusion of portions of an exon. Noncoding SLC4A9 cDNAs were recovered multiple times from different libraries. The 3' untranslated region is fragmented into six alternatively spliced exons and contains expressed Alu, LINE and MER repeats. SLC4A9 has two alternative stop codons and six polyadenylation sites. Its expression is largely restricted to the kidney. In silico approaches were used to characterize two additional novel SLC4A genes and to place SLC4A9 within the context of multiple paralogous gene clusters containing members of the epidermal growth factor (EGF), ankyrin (ANK) and fibroblast growth factor (FGF) families. Seven human EGF-SLC4A-ANK-FGF clusters were found. Conclusion: The novel sodium bicarbonate cotransporter-like gene SLC4A9 demonstrates abundant alternative mRNA processing. It belongs to a growing class of functionally diverse genes characterized by inefficient highly variable splicing. The evolutionary history of the EGF-SLC4A-ANK-FGF gene clusters involves multiple rounds of duplication, apparently followed by large insertions and deletions at paralogous loci and genome-wide gene shuffling. PMID:11305939

Garnet Pyroxenites from Kaula, Hawaii: Implications for Plume-Lithosphere Interaction

NASA Astrophysics Data System (ADS)

Bizimis, M.; Garcia, M. O.; Norman, M. D.

2006-12-01

The presence of garnet pyroxenite xenoliths on Oahu and Kaula Islands, Hawaii, provides the rare opportunity to investigate the composition of the deeper oceanic mantle lithosphere and the nature of plume-lithosphere interaction in two dimensions, downstream from the center of the Hawaiian plume. Kaula (60 miles SW of Kauai) is on the same bathymetric shallow as Kauai and the Kaula-Niihau-Kauai islands form a cross-trend relationship to the Hawaiian Island ridge. Here, we present the first Sr-Nd isotope data on clinopyroxenes (cpx) from Kaula pyroxenites, and we compare them with the Salt Lake Crater (SLC) pyroxenites from Oahu. The Kaula cpx major element compositions overlap those of the (more variable) SLC pyroxenites (e.g. Mg# = 0.79-0.83), except for their higher Al2O3 contents (9% vs. 5-8%) than the SLC. The Kaula cpx are LREE enriched with elevated Dy/Yb ratios, similar to the SLC pyroxenites and characteristic of the presence of garnet that preferentially incorporates the HREE. In Sr-Nd isotope space, the Kaula pyroxenite compositions (87Sr/86Sr= 0.70312-0.70326, ɛNd= 7.2-8.6) overlap those of both the Oahu-Kauai post erosional lavas and the SLC pyroxenites, falling at the isotopically depleted end of the Hawaiian lava compositions. The depleted Sr-Nd isotope compositions of the Kaula pyroxenites suggest that they are not related to the isotopically enriched shield stage Hawaiian lavas, either as a source material (i.e. recycled eclogite) or as cumulates. Their elevated 87Sr/86Sr ratios relative to MORB also suggests that they are not likely MORB-related cumulates. The similarities between the Oahu and Kaula pyroxenites, some 200 km apart, suggest the widespread presence of pyroxenitic material in the deeper (>60km) Pacific lithosphere between Oahu and Kaula-Kauai, as high pressure cumulates from melts isotopically similar to the secondary Hawaiian volcanism. The presence of this material within the lower lithosphere is consistent with seismic observations suggesting erosion and replacement of the deeper Pacific lithosphere by plume material, downstream from the center of the plume.

Cyclocreatine treatment improves cognition in mice with creatine transporter deficiency

PubMed Central

Kurosawa, Yuko; DeGrauw, Ton J.; Lindquist, Diana M.; Blanco, Victor M.; Pyne-Geithman, Gail J.; Daikoku, Takiko; Chambers, James B.; Benoit, Stephen C.; Clark, Joseph F.

2012-01-01

The second-largest cause of X-linked mental retardation is a deficiency in creatine transporter (CRT; encoded by SLC6A8), which leads to speech and language disorders with severe cognitive impairment. This syndrome, caused by the absence of creatine in the brain, is currently untreatable because CRT is required for creatine entry into brain cells. Here, we developed a brain-specific Slc6a8 knockout mouse (Slc6a8–/y) as an animal model of human CRT deficiency in order to explore potential therapies for this syndrome. The phenotype of the Slc6a8–/y mouse was comparable to that of human patients. We successfully treated the Slc6a8–/y mice with the creatine analog cyclocreatine. Brain cyclocreatine and cyclocreatine phosphate were detected after 9 weeks of cyclocreatine treatment in Slc6a8–/y mice, in contrast to the same mice treated with creatine or placebo. Cyclocreatine-treated Slc6a8–/y mice also exhibited a profound improvement in cognitive abilities, as seen with novel object recognition as well as spatial learning and memory tests. Thus, cyclocreatine appears promising as a potential therapy for CRT deficiency. PMID:22751104

Cyclocreatine treatment improves cognition in mice with creatine transporter deficiency.

PubMed

Kurosawa, Yuko; Degrauw, Ton J; Lindquist, Diana M; Blanco, Victor M; Pyne-Geithman, Gail J; Daikoku, Takiko; Chambers, James B; Benoit, Stephen C; Clark, Joseph F

2012-08-01

The second-largest cause of X-linked mental retardation is a deficiency in creatine transporter (CRT; encoded by SLC6A8), which leads to speech and language disorders with severe cognitive impairment. This syndrome, caused by the absence of creatine in the brain, is currently untreatable because CRT is required for creatine entry into brain cells. Here, we developed a brain-specific Slc6a8 knockout mouse (Slc6a8-/y) as an animal model of human CRT deficiency in order to explore potential therapies for this syndrome. The phenotype of the Slc6a8-/y mouse was comparable to that of human patients. We successfully treated the Slc6a8-/y mice with the creatine analog cyclocreatine. Brain cyclocreatine and cyclocreatine phosphate were detected after 9 weeks of cyclocreatine treatment in Slc6a8-/y mice, in contrast to the same mice treated with creatine or placebo. Cyclocreatine-treated Slc6a8-/y mice also exhibited a profound improvement in cognitive abilities, as seen with novel object recognition as well as spatial learning and memory tests. Thus, cyclocreatine appears promising as a potential therapy for CRT deficiency.

Uncertainty of the 20th century sea-level rise due to vertical land motion errors

NASA Astrophysics Data System (ADS)

Santamaría-Gómez, Alvaro; Gravelle, Médéric; Dangendorf, Sönke; Marcos, Marta; Spada, Giorgio; Wöppelmann, Guy

2017-09-01

Assessing the vertical land motion (VLM) at tide gauges (TG) is crucial to understanding global and regional mean sea-level changes (SLC) over the last century. However, estimating VLM with accuracy better than a few tenths of a millimeter per year is not a trivial undertaking and many factors, including the reference frame uncertainty, must be considered. Using a novel reconstruction approach and updated geodetic VLM corrections, we found the terrestrial reference frame and the estimated VLM uncertainty may contribute to the global SLC rate error by ± 0.2 mmyr-1. In addition, a spurious global SLC acceleration may be introduced up to ± 4.8 ×10-3 mmyr-2. Regional SLC rate and acceleration errors may be inflated by a factor 3 compared to the global. The difference of VLM from two independent Glacio-Isostatic Adjustment models introduces global SLC rate and acceleration biases at the level of ± 0.1 mmyr-1 and 2.8 ×10-3 mmyr-2, increasing up to 0.5 mm yr-1 and 9 ×10-3 mmyr-2 for the regional SLC. Errors in VLM corrections need to be budgeted when considering past and future SLC scenarios.

Three cysteine residues of SLC52A1, a receptor for the porcine endogenous retrovirus-A (PERV-A), play a critical role in cell surface expression and infectivity.

PubMed

Colon-Moran, Winston; Argaw, Takele; Wilson, Carolyn A

2017-07-01

Porcine endogenous retrovirus-A (PERV-A), a gammaretrovirus, infects human cells in vitro, thus raising the potential risk of cross-species transmission in xenotransplantation. Two members of the solute carrier family 52 (SLC52A1 and SLC52A2) are PERV-A receptors. Site-directed mutagenesis of the cDNA encoding SLC52A1 identified that only one of two putative glycosylation signals is occupied by glycans. In addition, we showed that glycosylation of SLC52A1 is not necessary for PERV-A receptor function. We also identified that at a minimum, three cysteine residues are sufficient for SLC52A1 cell surface expression. Mutation of cysteine at position 365 and either of the two cysteine residues in the C-terminal tail at positions 442 or 446 reduced SLC52A1 surface expression and PERV-A infection suggesting that these residues may contribute to overall structural stability and receptor function. Understanding interactions between PERV-A and its cellular receptor may provide novel strategies to prevent zoonotic infection in the setting of xenotransplantation. Published by Elsevier Inc.

The human gene SLC25A29, of solute carrier family 25, encodes a mitochondrial transporter of basic amino acids.

PubMed

Porcelli, Vito; Fiermonte, Giuseppe; Longo, Antonella; Palmieri, Ferdinando

2014-05-09

The human genome encodes 53 members of the solute carrier family 25 (SLC25), also called the mitochondrial carrier family, many of which have been shown to transport carboxylates, amino acids, nucleotides, and cofactors across the inner mitochondrial membrane, thereby connecting cytosolic and matrix functions. In this work, a member of this family, SLC25A29, previously reported to be a mitochondrial carnitine/acylcarnitine- or ornithine-like carrier, has been thoroughly characterized biochemically. The SLC25A29 gene was overexpressed in Escherichia coli, and the gene product was purified and reconstituted in phospholipid vesicles. Its transport properties and kinetic parameters demonstrate that SLC25A29 transports arginine, lysine, homoarginine, methylarginine and, to a much lesser extent, ornithine and histidine. Carnitine and acylcarnitines were not transported by SLC25A29. This carrier catalyzed substantial uniport besides a counter-exchange transport, exhibited a high transport affinity for arginine and lysine, and was saturable and inhibited by mercurial compounds and other inhibitors of mitochondrial carriers to various degrees. The main physiological role of SLC25A29 is to import basic amino acids into mitochondria for mitochondrial protein synthesis and amino acid degradation.

Pediatric radiation dosimetry for positron-emitting radionuclides using anthropomorphic phantoms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xie, Tianwu; Bolch, Wesley E.; Lee, Choonsik

2013-10-15

Purpose: Positron emission tomography (PET) plays an important role in the diagnosis, staging, treatment, and surveillance of clinically localized diseases. Combined PET/CT imaging exhibits significantly higher sensitivity, specificity, and accuracy than conventional imaging when it comes to detecting malignant tumors in children. However, the radiation dose from positron-emitting radionuclide to the pediatric population is a matter of concern since children are at a particularly high risk when exposed to ionizing radiation.Methods: The authors evaluate the absorbed fractions and specific absorbed fractions (SAFs) of monoenergy photons/electrons as well as S-values of 9 positron-emitting radionuclides (C-11, N-13, O-15, F-18, Cu-64, Ga-68, Rb-82,more » Y-86, and I-124) in 48 source regions for 10 anthropomorphic pediatric hybrid models, including the reference newborn, 1-, 5-, 10-, and 15-yr-old male and female models, using the Monte Carlo N-Particle eXtended general purpose Monte Carlo transport code.Results: The self-absorbed SAFs and S-values for most organs were inversely related to the age and body weight, whereas the cross-dose terms presented less correlation with body weight. For most source/target organ pairs, Rb-82 and Y-86 produce the highest self-absorbed and cross-absorbed S-values, respectively, while Cu-64 produces the lowest S-values because of the low-energy and high-frequency of electron emissions. Most of the total self-absorbed S-values are contributed from nonpenetrating particles (electrons and positrons), which have a linear relationship with body weight. The dependence of self-absorbed S-values of the two annihilation photons varies to the reciprocal of 0.76 power of the mass, whereas the self-absorbed S-values of positrons vary according to the reciprocal mass.Conclusions: The produced S-values for common positron-emitting radionuclides can be exploited for the assessment of radiation dose delivered to the pediatric population from various PET radiotracers used in clinical and research settings. The mass scaling method for positron-emitters can be used to derive patient-specific S-values from data of reference phantoms.« less

Measurement of cosmic ray positron and negatron spectra between 50 and 800 MeV. Ph.D. Thesis

NASA Technical Reports Server (NTRS)

Daugherty, J. K.

1974-01-01

A balloon-borne magnetic spectrometer was used to measure the spectra of cosmic ray positrons and negatrons at energies between 50 and 800 MeV. Comparisons of the separate positron and negatron spectra observed near the earth with their expected intensities in interstellar space can be used to investigate the complex (and variable) interaction of galactic cosmic rays with the expanding solar wind. The present measurements, which have established finite values or upper limits for the positron and negatron spectral between 50 and 800 MeV, have confirmed earlier evidence for the existence of a dominant component of negatrons from primary sources in the galaxy. The present results are shown to be consistent with the hypothesis that the positron component is in fact mainly attributable to collisions between cosmic ray nuclei and the interstellar gas. The estimate of the absolute intensities confirm the indications from neutron monitors that in 1972 the interplanetary cosmic ray intensities were already recovering toward their high levels observed in 1965.

28. VIEW SOUTH FROM SLC3W MST STATION 63. FOREGROUND LEFT: ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

28. VIEW SOUTH FROM SLC-3W MST STATION 63. FOREGROUND LEFT: THEODOLITE SHELTER (BLDG. 786) CENTER LEFT TO RIGHT: GLOBAL POSITIONING SYSTEM AZIMUTH STATION (BLDG. 775), PYROTECHNIC SHED (BLDG. 757), PORTABLE GUARD SHED, METEOROLOGICAL SHED (BLDG. 756), METEOROLOGICAL TOWER. BACKGROUND CENTER TO RIGHT: STORAGE SHED (BLDG. 776), LIQUID OXYGEN APRON, SLC-3E MST, TOP OF SLC-3E FUEL STORAGE TANK. - Vandenberg Air Force Base, Space Launch Complex 3, Launch Pad 3 West, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

Dipole anisotropy in cosmic electrons and positrons: inspection on local sources

DOE Office of Scientific and Technical Information (OSTI.GOV)

Manconi, S.; Donato, F.; Mauro, M. Di, E-mail: manconi@to.infn.it, E-mail: mdimauro@slac.stanford.edu, E-mail: donato@to.infn.it

The cosmic electrons and positrons have been measured with unprecedented statistics up to several hundreds GeV, thus permitting to explore the role that close single sources can have in shaping the flux at different energies. In the present analysis, we consider electrons and positrons in cosmic rays to be produced by spallations of hadron fluxes with the interstellar medium, by a smooth Supernova Remnant (SNR) population, by all the ATNF catalog pulsars, and by few discrete, local SNRs. We test several source models on the e {sup ++} e {sup −} and e {sup +} AMS-02 flux data. For themore » configurations compatible with the data, we compute the dipole anisotropy in e {sup ++} e {sup −}, e {sup +}, e {sup +}/ e {sup −} from single sources. Our study includes a dedicated analysis to the Vela SNR. We show that Fermi -LAT present data on dipole anisotropy of e {sup ++} e {sup −} start to explore some of the models for the Vela SNR selected by AMS-02 flux data. We also investigate how the observed anisotropy could result from a combination of local sources. Our analysis shows that the search of anisotropy in the lepton fluxes up to TeV energies can be an interesting tool for the inspection of properties of close SNRs, complementary to the high precision flux data.« less

Identification of the putative goldfish (Carassius auratus) magnesium transporter SLC41a1 and functional regulation in the gill, kidney, and intestine in response to dietary and environmental manipulations.

PubMed

Kodzhahinchev, Vladimir; Kovacevic, Drago; Bucking, Carol

2017-04-01

While magnesium requirements for teleost fish highlight the physiological importance of this cation for homeostasis, little is known regarding the molecular identity of transporters responsible for magnesium absorption or secretion. The recent characterization of the vertebrate magnesium transporter solute carrier 41a1 (SLC41a1) in the kidney of a euryhaline fish has provided a glimpse of possible moieties involved in piscine magnesium regulation. The present study obtained a novel SLC41a1 coding sequence for Carassius auratus and demonstrated ubiquitous expression in all tissues examined. Transcriptional regulation of SLC41a1 in response to dietary and environmental magnesium concentrations was observed across tissues. Specifically, decreased environmental magnesium correlated with decreased expression of SLC41a1 in the intestine, whereas the gill and kidney were unaffected. Dietary magnesium restriction correlated with decreased expression of SLC41a1 in the intestine and gill, while again no effects were detected in the kidney. Finally, elevated dietary magnesium correlated with increased expression of SLC41a1 in the kidney, while expression in the intestine and gill remained stable. Plasma magnesium was maintained in all treatments, and dietary assimilation efficiency increased with decreased dietary magnesium. Consumption of a single meal failed to impact SLC41a1 expression, and transcript abundance remained stable over the course of digestion in all treatments. Transcriptional regulation occurred between 7 and 14days following dietary and environmental manipulations and short-term regulation (e.g. <24h) was not observed. Overall the data supports transcriptional regulation of SLC41a1 reflecting a possible role in magnesium loss or secretion across tissues in fish. Copyright © 2017 Elsevier Inc. All rights reserved.

Dysfunction of the Cerebral Glucose Transporter SLC45A1 in Individuals with Intellectual Disability and Epilepsy.

PubMed

Srour, Myriam; Shimokawa, Noriaki; Hamdan, Fadi F; Nassif, Christina; Poulin, Chantal; Al Gazali, Lihadh; Rosenfeld, Jill A; Koibuchi, Noriyuki; Rouleau, Guy A; Al Shamsi, Aisha; Michaud, Jacques L

2017-05-04

Glucose transport across the blood brain barrier and into neural cells is critical for normal cerebral physiologic function. Dysfunction of the cerebral glucose transporter GLUT1 (encoded by SLC2A1) is known to result in epilepsy, intellectual disability (ID), and movement disorder. Using whole-exome sequencing, we identified rare homozygous missense variants (c.526C>T [p.Arg176Trp] and c.629C>T [p.Ala210Val]) in SLC45A1, encoding another cerebral glucose transporter, in two consanguineous multiplex families with moderate to severe ID, epilepsy, and variable neuropsychiatric features. The variants segregate with the phenotype in these families, affect well-conserved amino acids, and are predicted to be damaging by in silico programs. Intracellular glucose transport activity of the p.Arg176Trp and p.Ala210Val SLC45A1 variants, measured in transfected COS-7 cells, was approximately 50% (p = 0.013) and 33% (p = 0.008) lower, respectively, than that of intact SLC45A1. These results indicate that residues at positions 176 and 210 are critical for the glucose transport activity of SLC45A1. All together, our data strongly suggest that recessive mutations in SLC45A1 cause ID and epilepsy. SLC45A1 thus represents the second cerebral glucose transporter, in addition to GLUT1, to be involved in neurodevelopmental disability. Identification of additional individuals with mutations in SLC45A1 will allow better definition of the associated phenotypic spectrum and the exploration of potential targeted treatment options. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Comparison between SLC3A1 and SLC7A9 cystinuria patients and carriers: a need for a new classification.

PubMed

Dello Strologo, Luca; Pras, Elon; Pontesilli, Claudia; Beccia, Ercole; Ricci-Barbini, Vittorino; de Sanctis, Luisa; Ponzone, Alberto; Gallucci, Michele; Bisceglia, Luigi; Zelante, Leopoldo; Jimenez-Vidal, Maite; Font, Mariona; Zorzano, Antonio; Rousaud, Ferran; Nunes, Virginia; Gasparini, Paolo; Palacín, Manuel; Rizzoni, Gianfranco

2002-10-01

Recent developments in the genetics and physiology of cystinuria do not support the traditional classification, which is based on the excretion of cystine and dibasic amino acids in obligate heterozygotes. Mutations of only two genes (SLC3A1 and SLC7A9), identified by the International Cystinuria Consortium (ICC), have been found to be responsible for all three types of the disease. The ICC set up a multinational database and collected genetic and clinical data from 224 patients affected by cystinuria, 125 with full genotype definition. Amino acid urinary excretion patterns of 189 heterozygotes with genetic definition and of 83 healthy controls were also included. All SLC3A1 carriers and 14% of SLC7A9 carriers showed a normal amino acid urinary pattern (i.e., type I phenotype). The rest of the SLC7A9 carriers showed phenotype non-I (type III, 80.5%; type II, 5.5%). This makes the traditional classification imprecise. A new classification is needed: type A, due to two mutations of SLC3A1 (rBAT) on chromosome 2 (45.2% in our database); type B, due to two mutations of SLC7A9 on chromosome 19 (53.2% in this series); and a possible third type, AB (1.6%), with one mutation on each of the above-mentioned genes. Clinical data show that cystinuria is more severe in males than in females. The two types of cystinuria (A and B) had a similar outcome in this retrospective study, but the effect of the treatment could not be analyzed. Stone events do not correlate with amino acid urinary excretion. Renal function was clearly impaired in 17% of the patients.

Associations Between Neurotransmitter Genes and Fatigue and Energy Levels in Women Following Breast Cancer Surgery

PubMed Central

Eshragh, Jasmine; Dhruva, Anand; Paul, Steven M.; Cooper, Bruce A.; Mastick, Judy; Hamolsky, Deborah; Levine, Jon D.; Miaskowski, Christine; Kober, Kord M.

2016-01-01

Context Fatigue is a common problem in oncology patients. Less is known about decrements in energy levels and the mechanisms that underlie both fatigue and energy. Objectives In patients with breast cancer, variations in neurotransmitter genes between Lower and Higher Fatigue latent classes and between the Higher and Lower Energy latent classes were evaluated. Methods Patients completed assessments prior to and monthly for 6 months following surgery. Growth mixture modeling was used to identify distinct latent classes for fatigue severity and energy levels. Thirty candidate genes involved in various aspects of neurotransmission were evaluated. Results Eleven single nucleotide polymorphisms (SNPs) or haplotypes (i.e., ADRB2 rs1042718, BDNF rs6265, COMT rs9332377, CYP3A4 rs4646437, GALR1 rs949060, GCH1 rs3783642, NOS1 rs9658498, NOS1 rs2293052, NPY1R Haplotype A04, SLC6A2 rs17841327 and 5HTTLPR + rs25531 in SLC6A4) were associated with latent class membership for fatigue. Seven SNPs or haplotypes (i.e., NOS1 rs471871, SLC6A1 rs2675163, SLC6A1 Haplotype D01, SLC6A2 rs36027, SLC6A3 rs37022, SLC6A4 rs2020942, and TAC1 rs2072100) were associated with latent class membership for energy. Three of thirteen genes (i.e., NOS1, SLC6A2, SLC6A4) were associated with latent class membership for both fatigue and energy. Conclusions Molecular findings support the hypothesis that fatigue and energy are distinct, yet related symptoms. Results suggest that a large number of neurotransmitters play a role in the development and maintenance of fatigue and energy levels in breast cancer patients. PMID:27720787

T7. PHARMACOGENETIC OF TARDIVE DYSKINESIA -- A FOLLOW-UP ON THE VALBENAZINE TARGET VMAT2/SLC18A2

PubMed Central

Zai, Clement; Tiwari, Arun; Mueller, Daniel; Voineskos, Aristotle; Potkin, Steven G; Lieberman, Jeffrey; Meltzer, Herbert; Remington, Gary; Kennedy, James

2018-01-01

Abstract Background Tardive dyskinesia (TD) is a motor side effect that may arise after long-term treatment of antipsychotic drugs. Its etiology is not well understood, but a number of risk factors have been associated with TD. TD occurrence appears to be familial, thus suggesting a genetic component. We previously reported on an association between the SLC18A2 gene that codes for the vesicular monoamine transporter 2 (VMAT2) that packages monoamines including dopamine from the cytoplasm into synaptic vesicles (Zai et al, 2013). In the present study, we examined the dopamine transporter gene SLC6A3 by itself and in conjunction with SLC18A2 for possible association with TD. Methods We genotyped and analyzed the variable-number tandem repeat (VNTR) polymorphism in the 3’ untranslated region of the SLC6A3 gene in our European sample of 187 schizophrenia/schizoaffective disorder patients assessed for TD occurrence based on the Abnormal Involuntary Movement Scale (AIMS). We also explored the interaction between the VNTR and the TD-associated SLC18A2 marker rs363224. Results Our preliminary analysis did not show the SLC6A3 VNTR to be associated with TD occurrence or severity. There also appeared to be no significant interaction between SLC6A3 VNTR and SLC18A2 rs363224 in TD occurrence or severity (p>0.05). Discussion Our findings did not support a major role of the dopamine transporter gene in TD risk or severity, but we will examine additional putative functional markers in this gene.

Bile Acid-regulated Peroxisome Proliferator-activated Receptor-α (PPARα) Activity Underlies Circadian Expression of Intestinal Peptide Absorption Transporter PepT1/Slc15a1*

PubMed Central

Okamura, Ayako; Koyanagi, Satoru; Dilxiat, Adila; Kusunose, Naoki; Chen, Jia Jun; Matsunaga, Naoya; Shibata, Shigenobu; Ohdo, Shigehiro

2014-01-01

Digested proteins are mainly absorbed as small peptides composed of two or three amino acids. The intestinal absorption of small peptides is mediated via only one transport system: the proton-coupled peptide transporter-1 (PepT1) encoded from the soluble carrier protein Slc15a1. In mammals, intestinal expression of PepT1/Slc15a1 oscillates during the daily feeding cycle. Although the oscillation in the intestinal expression of PepT1/Slc15a1 is suggested to be controlled by molecular components of circadian clock, we demonstrated here that bile acids regulated the oscillation of PepT1/Slc15a1 expression through modulating the activity of peroxisome proliferator-activated receptor α (PPARα). Nocturnally active mice mainly consumed their food during the dark phase. PPARα activated the intestinal expression of Slc15a1 mRNA during the light period, and protein levels of PepT1 peaked before the start of the dark phase. After food intake, bile acids accumulated in intestinal epithelial cells. Intestinal accumulated bile acids interfered with recruitment of co-transcriptional activator CREB-binding protein/p300 on the promoter region of Slc15a1 gene, thereby suppressing PPARα-mediated transactivation of Slc15a1. The time-dependent suppression of PPARα-mediated transactivation by bile acids caused an oscillation in the intestinal expression of PepT1/Slc15a1 during the daily feeding cycle that led to circadian changes in the intestinal absorption of small peptides. These findings suggest a molecular clock-independent mechanism by which bile acid-regulated PPARα activity governs the circadian expression of intestinal peptide transporter. PMID:25016014

Novel high-energy physics studies using intense lasers and plasmas

DOE Office of Scientific and Technical Information (OSTI.GOV)

Leemans, Wim P.; Bulanov, Stepan; Esarey, Eric

2015-06-29

In the framework of the project “Novel high-energy physics studies using intense lasers and plasmas” we conducted the study of ion acceleration and “flying mirrors” with high intensity lasers in order to develop sources of ion beams and high frequency radiation for different applications. Since some schemes of laser ion acceleration are also considered a good source of “flying mirrors”, we proposed to investigate the mechanisms of “mirror” formation. As a result we were able to study the laser ion acceleration from thin foils and near critical density targets. We identified several fundamental factors limiting the acceleration in the RPAmore » regime and proposed the target design to compensate these limitations. In the case of near critical density targets, we developed a concept for the laser driven ion source for the hadron therapy. Also we studied the mechanism of “flying mirror” generation during the intense laser interaction with thin solid density targets. As for the laser-based positron creation and capture we initially proposed to study different regimes of positron beam generation and positron beam cooling. Since the for some of these schemes a good quality electron beam is required, we studied the generation of ultra-low emittance electron beams. In order to understand the fundamental physics of high energy electron beam interaction with high intensity laser pulses, which may affect the efficient generation of positron beams, we studied the radiation reaction effects.« less

Inhibition of SLC1A5 sensitizes colorectal cancer to cetuximab.

PubMed

Ma, Huanrong; Wu, Zhenzhen; Peng, Jianjun; Li, Yang; Huang, Hongxiang; Liao, Yi; Zhou, Minyu; Sun, Li; Huang, Na; Shi, Min; Bin, Jianping; Liao, Yulin; Rao, Jinjun; Wang, Lin; Liao, Wangjun

2018-06-15

Cetuximab resistance is a key barrier in treating metastatic colorectal cancer (mCRC). Targeting of metabolic resources import could resensitize drug-resistant cancer cells to anticancer treatments. Here we showed that the expression of the glutamine transporter solute carrier 1 family member 5 (SLC1A5) in clinical CRC samples of patients resisted to cetuximab was significantly higher than in those of patients responded to cetuximab. Inhibition of SLC1A5 by shRNA-mediated gene silencing or pharmacological inhibitor significantly suppressed the growth of CRC. Moreover, inhibition of SLC1A5 significantly enhanced the inhibitory efficacy of cetuximab on CRC proliferation both in vitro and in vivo. Mechanistically, SLC1A5 inhibition facilitated EGFR degradation through the ubiquitin-proteasome pathway, and decreased the expression of nuclear EGFR, both of which might have contribution to the improved response to cetuximab. This study provides the metabolic molecule SLC1A5 as a potential therapeutic target to increase the efficacy of cetuximab on CRC. © 2018 UICC.

Progress toward magnetic confinement of a positron-electron plasma: nearly 100% positron injection efficiency into a dipole trap

NASA Astrophysics Data System (ADS)

Stoneking, Matthew

2017-10-01

The hydrogen atom provides the simplest system and in some cases the most precise one for comparing theory and experiment in atomics physics. The field of plasma physics lacks an experimental counterpart, but there are efforts underway to produce a magnetically confined positron-electron plasma that promises to represent the simplest plasma system. The mass symmetry of positron-electron plasma makes it particularly tractable from a theoretical standpoint and many theory papers have been published predicting modified wave and stability properties in these systems. Our approach is to utilize techniques from the non-neutral plasma community to trap and accumulate electrons and positrons prior to mixing in a magnetic trap with good confinement properties. Ultimately we aim to use a levitated superconducting dipole configuration fueled by positrons from a reactor-based positron source and buffer-gas trap. To date we have conducted experiments to characterize and optimize the positron beam and test strategies for injecting positrons into the field of a supported permanent magnet by use of ExB drifts and tailored static and dynamic potentials applied to boundary electrodes and to the magnet itself. Nearly 100% injection efficiency has been achieved under certain conditions and some fraction of the injected positrons are confined for as long as 400 ms. These results are promising for the next step in the project which is to use an inductively energized high Tc superconducting coil to produce the dipole field, initially in a supported configuration, but ultimately levitated using feedback stabilization. Work performed with the support of the German Research Foundation (DFG), JSPS KAKENHI, NIFS Collaboration Research Program, and the UCSD Foundation.

Defect studies of nanocrystalline zirconia powders and sintered ceramics

NASA Astrophysics Data System (ADS)

Čížek, Jakub; Melikhova, Oksana; Procházka, Ivan; Kuriplach, Jan; Kužel, Radomír; Brauer, Gerhard; Anwand, Wolfgang; Konstantinova, Tatyana E.; Danilenko, Igor A.

2010-01-01

The main objective of the present paper is to communicate a study of defects behavior in zirconia-based nanomaterials—pressure-compacted yttria-stabilized zirconia (YSZ) nanopowders with different contents of Y2O3 and ceramics obtained by sintering the YZS nanopowders. In addition, YZS single crystals were also investigated. Positron annihilation techniques including positron lifetime and coincidence Doppler broadening with a conventional positron source and Doppler broadening experiments on a monoenergetic positron beam were involved in this study as the principal tools. These techniques were supplemented with transmission electron microscopy and x-ray diffraction observations. In order to get better support of the experimental data interpretation, the state-of-art theoretical calculations of positron parameters were performed for the perfect ZrO2 lattice and selected defect configurations in the YSZ. Theoretical calculations have indicated that neither the oxygen vacancies nor their neutral complexes with substitutional yttrium atoms are capable of positron trapping. On the other hand, the zirconium vacancies are deep positron traps and obviously are responsible for the saturated positron trapping observed in the YSZ single crystals. In the compacted YSZ nanopowders, a majority of positrons is trapped either in the vacancylike defects situated in the negative space-charge layers along grain boundaries (τ1≈185ps) or in vacancy clusters at intersections of grain boundaries (τ2≈370ps) . The intensity ratio I2/I1 was found to be correlated with the mean grain size d as I2/I1˜d-2 . A small fraction of positrons (≈10%) form positronium in large pores (τ3≈2ns,τ4≈30ns) . A significant grain growth during sintering of the YSZ nanopowders above 1000°C was observed.

Decreased miR-106a inhibits glioma cell glucose uptake and proliferation by targeting SLC2A3 in GBM.

PubMed

Dai, Dong-Wei; Lu, Qiong; Wang, Lai-Xing; Zhao, Wen-Yuan; Cao, Yi-Qun; Li, Ya-Nan; Han, Guo-Sheng; Liu, Jian-Min; Yue, Zhi-Jian

2013-10-14

MiR-106a is frequently down-regulated in various types of human cancer. However the underlying mechanism of miR-106a involved in glioma remains elusive. The association of miR-106a with glioma grade and patient survival was analyzed. The biological function and target of miR-106a were determined by bioinformatic analysis and cell experiments (Western blot, luciferase reporter, cell cycle, ntracellular ATP production and glucose uptake assay). Finally, rescue expression of its target SLC2A3 was used to test the role of SLC2A3 in miR-106a-mediated cell glycolysis and proliferation. Here we showed that miR-106a was a tumor suppressor miRNA was involved in GBM cell glucose uptake and proliferation. Decreased miR-106a in GBM tissues and conferred a poor survival of GBM patients. SLC2A3 was identified as a core target of miR-106a in GBM cells. Inhibition of SLC2A3 by miR-106a attenuated cell proliferation and inhibited glucose uptake. In addition, for each biological process we identified ontology-associated transcripts that significantly correlated with SLC2A3 expression. Finally, the expression of SLC2A3 largely abrogated miR-106a-mediated cell proliferation and glucose uptake in GBM cells. Taken together, miR-106a and SLC2A3 could be potential therapeutic approaches for GBM.

Functional characterization of 5-oxoproline transport via SLC16A1/MCT1.

PubMed

Sasaki, Shotaro; Futagi, Yuya; Kobayashi, Masaki; Ogura, Jiro; Iseki, Ken

2015-01-23

Thyrotropin-releasing hormone is a tripeptide that consists of 5-oxoproline, histidine, and proline. The peptide is rapidly metabolized by various enzymes. 5-Oxoproline is produced by enzymatic hydrolysis in a variety of peptides. Previous studies showed that 5-oxoproline could become a possible biomarker for autism spectrum disorders. Here we demonstrate the involvement of SLC16A1 in the transport of 5-oxoproline. An SLC16A1 polymorphism (rs1049434) was recently identified. However, there is no information about the effect of the polymorphism on SLC16A1 function. In this study, the polymorphism caused an observable change in 5-oxoproline and lactate transport via SLC16A1. The Michaelis constant (Km) was increased in an SLC16A1 mutant compared with that in the wild type. In addition, the proton concentration required to produce half-maximal activation of transport activity (K0.5, H (+)) was increased in the SLC16A1 mutant compared with that in the wild type. Furthermore, we examined the transport of 5-oxoproline in T98G cells as an astrocyte cell model. Despite the fact that 5-oxoproline is an amino acid derivative, Na(+)-dependent and amino acid transport systems scarcely contributed to 5-oxoproline transport. Based on our findings, we conclude that H(+)-coupled 5-oxoproline transport is mediated solely by SLC16A1 in the cells. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Functional Testing of SLC26A4 Variants—Clinical and Molecular Analysis of a Cohort with Enlarged Vestibular Aqueduct from Austria

PubMed Central

Bernardinelli, Emanuele; Nofziger, Charity; Patsch, Wolfgang; Rasp, Gerd; Paulmichl, Markus; Dossena, Silvia

2018-01-01

The prevalence and spectrum of sequence alterations in the SLC26A4 gene, which codes for the anion exchanger pendrin, are population-specific and account for at least 50% of cases of non-syndromic hearing loss associated with an enlarged vestibular aqueduct. A cohort of nineteen patients from Austria with hearing loss and a radiological alteration of the vestibular aqueduct underwent Sanger sequencing of SLC26A4 and GJB2, coding for connexin 26. The pathogenicity of sequence alterations detected was assessed by determining ion transport and molecular features of the corresponding SLC26A4 protein variants. In this group, four uncharacterized sequence alterations within the SLC26A4 coding region were found. Three of these lead to protein variants with abnormal functional and molecular features, while one should be considered with no pathogenic potential. Pathogenic SLC26A4 sequence alterations were only found in 12% of patients. SLC26A4 sequence alterations commonly found in other Caucasian populations were not detected. This survey represents the first study on the prevalence and spectrum of SLC26A4 sequence alterations in an Austrian cohort and further suggests that genetic testing should always be integrated with functional characterization and determination of the molecular features of protein variants in order to unequivocally identify or exclude a causal link between genotype and phenotype. PMID:29320412

SLC25 Family Member Genetic Interactions Identify a Role for HEM25 in Yeast Electron Transport Chain Stability.

PubMed

Dufay, J Noelia; Fernández-Murray, J Pedro; McMaster, Christopher R

2017-06-07

The SLC25 family member SLC25A38 (Hem25 in yeast) was recently identified as a mitochondrial glycine transporter that provides substrate to initiate heme/hemoglobin synthesis. Mutations in the human SLC25A38 gene cause congenital sideroblastic anemia. The full extent to which SLC25 family members coregulate heme synthesis with other mitochondrial functions is not clear. In this study, we surveyed 29 nonessential SLC25 family members in Saccharomyces cerevisiae for their ability to support growth in the presence and absence of HEM25 Six SLC25 family members were identified that were required for growth or for heme synthesis in cells lacking Hem25 function. Importantly, we determined that loss of function of the SLC25 family member Flx1, which imports FAD into mitochondria, together with loss of function of Hem25, resulted in inability to grow on media that required yeast cells to supply energy using mitochondrial respiration. We report that specific components of complexes of the electron transport chain are decreased in the absence of Flx1 and Hem25 function. In addition, we show that mitochondria from flx1 Δ hem25 Δ cells contain uncharacterized Cox2-containing high molecular weight aggregates. The functions of Flx1 and Hem25 provide a facile explanation for the decrease in heme level, and in specific electron transport chain complex components. Copyright © 2017 Dufay et al.

Is mini-laparoscopic cholecystectomy any better than the gold standard?: A comparative study.

PubMed

Shaikh, Haris R; Abbas, Asad; Aleem, Salik; Lakhani, Miqdad R

2017-01-01

Mini-laparoscopic cholecystectomy (MLC) has widened the horizons of modern laparoscopic surgery. Standard four port laparoscopic cholecystectomy (SLC), which has long been established as the "Gold Standard" for gall bladder diseases, is under reconsideration following the advent of further minimally-invasive procedures including MLC. Our study aims to provide a comparison between MLC and SLC and assesses whether MLC has any added benefits. Patients with symptomatic gall bladder disease undergoing MLC or SLC during the 2.5-month period were included in the study. Thirty-two patients underwent MLC while SLC was performed on 40 patients by the same surgeon. Data was collected prospectively and analysed retrospectively using a predesigned questionnaire. In our study, both the groups had similar age, body mass index (BMI) and gender distribution. No cases of MLC required insertion of additional ports. The mean operative time for MLC was 38.2 min (33-61 min), which is longer than SLC; but it was not statistically significant. There was no significant difference in mean operative blood loss, postoperative pain, analgesia requirement and mobilization. Patients who underwent MLC were able to return to normal activity earlier than patients undergoing SLC (P < 0.01). Our experience suggests that MLC can safely be used as an alternative to SLC. Compared to SLC, it has the added benefit of an early return to work along with excellent cosmetic results. Further large scale trials are required to prove any additional benefit of MLC.

Is mini-laparoscopic cholecystectomy any better than the gold standard?: A comparative study

PubMed Central

Shaikh, Haris R.; Abbas, Asad; Aleem, Salik; Lakhani, Miqdad R.

2017-01-01

BACKGROUND: Mini-laparoscopic cholecystectomy (MLC) has widened the horizons of modern laparoscopic surgery. Standard four port laparoscopic cholecystectomy (SLC), which has long been established as the “Gold Standard” for gall bladder diseases, is under reconsideration following the advent of further minimally-invasive procedures including MLC. Our study aims to provide a comparison between MLC and SLC and assesses whether MLC has any added benefits. MATERIALS AND METHODS: Patients with symptomatic gall bladder disease undergoing MLC or SLC during the 2.5-month period were included in the study. Thirty-two patients underwent MLC while SLC was performed on 40 patients by the same surgeon. Data was collected prospectively and analysed retrospectively using a predesigned questionnaire. RESULTS: In our study, both the groups had similar age, body mass index (BMI) and gender distribution. No cases of MLC required insertion of additional ports. The mean operative time for MLC was 38.2 min (33-61 min), which is longer than SLC; but it was not statistically significant. There was no significant difference in mean operative blood loss, postoperative pain, analgesia requirement and mobilization. Patients who underwent MLC were able to return to normal activity earlier than patients undergoing SLC (P < 0.01). CONCLUSION: Our experience suggests that MLC can safely be used as an alternative to SLC. Compared to SLC, it has the added benefit of an early return to work along with excellent cosmetic results. Further large scale trials are required to prove any additional benefit of MLC. PMID:27251827

Loss of the anion exchanger DRA (Slc26a3), or PAT1 (Slc26a6), alters sulfate transport by the distal ileum and overall sulfate homeostasis.

PubMed

Whittamore, Jonathan M; Hatch, Marguerite

2017-09-01

The ileum is considered the primary site of inorganic sulfate ([Formula: see text]) absorption. In the present study, we explored the contributions of the apical chloride/bicarbonate (Cl - /[Formula: see text]) exchangers downregulated in adenoma (DRA; Slc26a3), and putative anion transporter 1 (PAT1; Slc26a6), to the underlying transport mechanism. Transepithelial 35 [Formula: see text] and 36 Cl - fluxes were determined across isolated, short-circuited segments of the distal ileum from wild-type (WT), DRA-knockout (KO), and PAT1-KO mice, together with measurements of urine and plasma sulfate. The WT distal ileum supported net sulfate absorption [197.37 ± 13.61 (SE) nmol·cm -2 ·h -1 ], but neither DRA nor PAT1 directly contributed to the unidirectional mucosal-to-serosal flux ([Formula: see text]), which was sensitive to serosal (but not mucosal) DIDS, dependent on Cl - , and regulated by cAMP. However, the absence of DRA significantly enhanced net sulfate absorption by one-third via a simultaneous rise in [Formula: see text] and a 30% reduction to the secretory serosal-to-mucosal flux ([Formula: see text]). We propose that DRA, together with PAT1, contributes to [Formula: see text] by mediating sulfate efflux across the apical membrane. Associated with increased ileal sulfate absorption in vitro, plasma sulfate was 61% greater, and urinary sulfate excretion ( U SO4 ) 2.2-fold higher, in DRA-KO mice compared with WT controls, whereas U SO4 was increased 1.8-fold in PAT1-KO mice. These alterations to sulfate homeostasis could not be accounted for by any changes to renal sulfate handling suggesting that the source of this additional sulfate was intestinal. In summary, we characterized transepithelial sulfate fluxes across the mouse distal ileum demonstrating that DRA (and to a lesser extent, PAT1) secretes sulfate with significant implications for intestinal sulfate absorption and overall homeostasis. NEW & NOTEWORTHY Sulfate is an essential anion that is actively absorbed from the small intestine involving members of the Slc26 gene family. Here, we show that the main intestinal chloride transporter Slc26a3, known as downregulated in adenoma (DRA), also handles sulfate and contributes to its secretion into the lumen. In the absence of functional DRA (as in the disease congenital chloride diarrhea), net intestinal sulfate absorption was significantly enhanced resulting in substantial alterations to overall sulfate homeostasis. Copyright © 2017 the American Physiological Society.

Study of defects in an electroresistive Au/La2/3Sr1/3MnO3/SrTiO3(001) heterostructure by positron annihilation

NASA Astrophysics Data System (ADS)

Ferragut, R.; Dupaquier, A.; Brivio, S.; Bertacco, R.; Egger, W.

2011-09-01

Defects in an ultrathin Au/La2/3Sr1/3MnO3/SrTiO3 (Au/LSMO/STO) heterostructure displaying electroresistive behavior were studied using variable energy positron annihilation spectroscopy. Vacancy-like defects were found to be the dominant positron traps in the LSMO and STO thin perovskite oxides with a number density >1017 cm-3 and 2 × 1017 cm-3 in the STO substrate. High defect density was revealed by strong positron trapping at the Au/LSMO interface. Oxygen deficiency in LSMO would be the main source of these traps. Besides, a low density of sub-nano voids of ˜6 Å was found in the substrate and in the thin LSMO/STO films.

10. PAYLOAD CONTROL CONSOLE NEAR SOUTH WALL OF SLC3W CONTROL ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

10. PAYLOAD CONTROL CONSOLE NEAR SOUTH WALL OF SLC-3W CONTROL ROOM. DECALS ON CONSOLE IN FOREGROUND INDICATE PAYLOAD PROGRAMS LAUNCHED FROM SLC-3W. - Vandenberg Air Force Base, Space Launch Complex 3, Launch Operations Building, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

Regulation of the human SLC25A20 expression by peroxisome proliferator-activated receptor alpha in human hepatoblastoma cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tachibana, Keisuke, E-mail: nya@phs.osaka-u.ac.jp; Takeuchi, Kentaro; Inada, Hirohiko

2009-11-20

Solute carrier family 25, member 20 (SLC25A20) is a key molecule that transfers acylcarnitine esters in exchange for free carnitine across the mitochondrial membrane in the mitochondrial {beta}-oxidation. The peroxisome proliferator-activated receptor alpha (PPAR{alpha}) is a ligand-activated transcription factor that plays an important role in the regulation of {beta}-oxidation. We previously established tetracycline-regulated human cell line that can be induced to express PPAR{alpha} and found that PPAR{alpha} induces the SLC25A20 expression. In this study, we analyzed the promoter region of the human slc25a20 gene and showed that PPAR{alpha} regulates the expression of human SLC25A20 via the peroxisome proliferator responsive element.

Bovine and murine models highlight novel roles for SLC25A46 in mitochondrial dynamics and metabolism, with implications for human and animal health

PubMed Central

Vaiman, Anne; Beauvallet, Christian; Floriot, Sandrine; Rodriguez, Sabrina; Vilotte, Marthe; Boulanger, Laurent; Albaric, Olivier; Guillaume, François; Boukadiri, Abdelhak; Richard, Laurence; Bertaud, Maud; Timsit, Edouard; Guatteo, Raphaël; Jaffrézic, Florence; Calvel, Pierre; Helary, Louise; Mahla, Rachid; Esquerré, Diane; Péchoux, Christine; Liuu, Sophie; Boichard, Didier; Slama, Abdelhamid; Vilotte, Jean-Luc

2017-01-01

Neuropathies are neurodegenerative diseases affecting humans and other mammals. Many genetic causes have been identified so far, including mutations of genes encoding proteins involved in mitochondrial dynamics. Recently, the “Turning calves syndrome”, a novel sensorimotor polyneuropathy was described in the French Rouge-des-Prés cattle breed. In the present study, we determined that this hereditary disease resulted from a single nucleotide substitution in SLC25A46, a gene encoding a protein of the mitochondrial carrier family. This mutation caused an apparent damaging amino-acid substitution. To better understand the function of this protein, we knocked out the Slc25a46 gene in a mouse model. This alteration affected not only the nervous system but also altered general metabolism, resulting in premature mortality. Based on optic microscopy examination, electron microscopy and on biochemical, metabolic and proteomic analyses, we showed that the Slc25a46 disruption caused a fusion/fission imbalance and an abnormal mitochondrial architecture that disturbed mitochondrial metabolism. These data extended the range of phenotypes associated with Slc25a46 dysfunction. Moreover, this Slc25a46 knock-out mouse model should be useful to further elucidate the role of SLC25A46 in mitochondrial dynamics. PMID:28376083

Impaired riboflavin transport due to missense mutations in SLC52A2 causes Brown-Vialetto-Van Laere syndrome.

PubMed

Haack, Tobias B; Makowski, Christine; Yao, Yoshiaki; Graf, Elisabeth; Hempel, Maja; Wieland, Thomas; Tauer, Ulrike; Ahting, Uwe; Mayr, Johannes A; Freisinger, Peter; Yoshimatsu, Hiroki; Inui, Ken; Strom, Tim M; Meitinger, Thomas; Yonezawa, Atsushi; Prokisch, Holger

2012-11-01

Brown-Vialetto-Van Laere syndrome (BVVLS [MIM 211530]) is a rare neurological disorder characterized by infancy onset sensorineural deafness and ponto-bulbar palsy. Mutations in SLC52A3 (formerly C20orf54), coding for riboflavin transporter 2 (hRFT2), have been identified as the molecular genetic correlate in several individuals with BVVLS. Exome sequencing of just one single case revealed that compound heterozygosity for two pathogenic mutations in the SLC52A2 gene coding for riboflavin transporter 3 (hRFT3), another member of the riboflavin transporter family, is also associated with BVVLS. Overexpression studies confirmed that the gene products of both mutant alleles have reduced riboflavin transport activities. While mutations in SLC52A3 cause decreased plasma riboflavin levels, concordant with a role of SLC52A3 in riboflavin uptake from food, the SLC52A2-mutant individual had normal plasma riboflavin concentrations, a finding in line with a postulated function of SLC52A2 in riboflavin uptake from blood into target cells. Our results contribute to the understanding of human riboflavin metabolism and underscore its role in the pathogenesis of BVVLS, thereby providing a rational basis for a high-dose riboflavin treatment.

The Human Gene SLC25A29, of Solute Carrier Family 25, Encodes a Mitochondrial Transporter of Basic Amino Acids*

PubMed Central

Porcelli, Vito; Fiermonte, Giuseppe; Longo, Antonella; Palmieri, Ferdinando

2014-01-01

The human genome encodes 53 members of the solute carrier family 25 (SLC25), also called the mitochondrial carrier family, many of which have been shown to transport carboxylates, amino acids, nucleotides, and cofactors across the inner mitochondrial membrane, thereby connecting cytosolic and matrix functions. In this work, a member of this family, SLC25A29, previously reported to be a mitochondrial carnitine/acylcarnitine- or ornithine-like carrier, has been thoroughly characterized biochemically. The SLC25A29 gene was overexpressed in Escherichia coli, and the gene product was purified and reconstituted in phospholipid vesicles. Its transport properties and kinetic parameters demonstrate that SLC25A29 transports arginine, lysine, homoarginine, methylarginine and, to a much lesser extent, ornithine and histidine. Carnitine and acylcarnitines were not transported by SLC25A29. This carrier catalyzed substantial uniport besides a counter-exchange transport, exhibited a high transport affinity for arginine and lysine, and was saturable and inhibited by mercurial compounds and other inhibitors of mitochondrial carriers to various degrees. The main physiological role of SLC25A29 is to import basic amino acids into mitochondria for mitochondrial protein synthesis and amino acid degradation. PMID:24652292

MYCN amplification confers enhanced folate dependence and methotrexate sensitivity in neuroblastoma

PubMed Central

Lau, Diana T.; Flemming, Claudia L.; Gherardi, Samuele; Perini, Giovanni; Oberthuer, André; Fischer, Matthias; Juraeva, Dilafruz; Brors, Benedikt; Xue, Chengyuan; Norris, Murray D.; Marshall, Glenn M.; Haber, Michelle

2015-01-01

MYCN amplification occurs in 20% of neuroblastomas and is strongly related to poor clinical outcome. We have identified folate-mediated one-carbon metabolism as highly upregulated in neuroblastoma tumors with MYCN amplification and have validated this finding experimentally by showing that MYCN amplified neuroblastoma cell lines have a higher requirement for folate and are significantly more sensitive to the antifolate methotrexate than cell lines without MYCN amplification. We have demonstrated that methotrexate uptake in neuroblastoma cells is mediated principally by the reduced folate carrier (RFC; SLC19A1), that SLC19A1 and MYCN expression are highly correlated in both patient tumors and cell lines, and that SLC19A1 is a direct transcriptional target of N-Myc. Finally, we assessed the relationship between SLC19A1 expression and patient survival in two independent primary tumor cohorts and found that SLC19A1 expression was associated with increased risk of relapse or death, and that SLC19A1 expression retained prognostic significance independent of age, disease stage and MYCN amplification. This study adds upregulation of folate-mediated one-carbon metabolism to the known consequences of MYCN amplification, and suggests that this pathway might be targeted in poor outcome tumors with MYCN amplification and high SLC19A1 expression. PMID:25860940

Major involvement of Na(+) -dependent multivitamin transporter (SLC5A6/SMVT) in uptake of biotin and pantothenic acid by human brain capillary endothelial cells.

PubMed

Uchida, Yasuo; Ito, Katsuaki; Ohtsuki, Sumio; Kubo, Yoshiyuki; Suzuki, Takashi; Terasaki, Tetsuya

2015-07-01

The purpose of this study was to clarify the expression of Na(+) -dependent multivitamin transporter (SLC5A6/SMVT) and its contribution to the supply of biotin and pantothenic acid to the human brain via the blood-brain barrier. DNA microarray and immunohistochemical analyses confirmed that SLC5A6 is expressed in microvessels of human brain. The absolute expression levels of SLC5A6 protein in isolated human and monkey brain microvessels were 1.19 and 0.597 fmol/μg protein, respectively, as determined by a quantitative targeted absolute proteomics technique. Using an antibody-free method established by Kubo et al. (2015), we found that SLC5A6 was preferentially localized at the luminal membrane of brain capillary endothelium. Knock-down analysis using SLC5A6 siRNA showed that SLC5A6 accounts for 88.7% and 98.6% of total [(3) H]biotin and [(3) H]pantothenic acid uptakes, respectively, by human cerebral microvascular endothelial cell line hCMEC/D3. SLC5A6-mediated transport in hCMEC/D3 was markedly inhibited not only by biotin and pantothenic acid, but also by prostaglandin E2, lipoic acid, docosahexaenoic acid, indomethacin, ketoprofen, diclofenac, ibuprofen, phenylbutazone, and flurbiprofen. This study is the first to confirm expression of SLC5A6 in human brain microvessels and to provide evidence that SLC5A6 is a major contributor to luminal uptake of biotin and pantothenic acid at the human blood-brain barrier. In humans, it was unclear (not concluded) about what transport system at the blood-brain barrier (BBB) is responsible for the brain uptakes of two vitamins, biotin and pantothenic acid, which are necessary for brain proper function. This study clarified for the first time that the solute carrier 5A6/Na(+) -dependent multivitamin transporter SLC5A6/SMVT is responsible for the supplies of biotin and pantothenic acid into brain across the BBB in humans. DHA, docosahexaenoic acid; NSAID, non-steroidal anti-inflammatory drug; PGE2, prostaglandin E2. © 2015 International Society for Neurochemistry.

Cosmic ray electrons, positrons and the synchrotron emission of the Galaxy: consistent analysis and implications

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bernardo, Giuseppe Di; Evoli, Carmelo; Gaggero, Daniele

2013-03-01

A multichannel analysis of cosmic ray electron and positron spectra and of the diffuse synchrotron emission of the Galaxy is performed by using the DRAGON code. This study is aimed at probing the interstellar electron source spectrum down to E ∼< 1GeV and at constraining several propagation parameters. We find that above 4GeV the e{sup −} source spectrum is compatible with a power-law of index ∼ 2.5. Below 4GeV instead it must be significantly suppressed and the total lepton spectrum is dominated by secondary particles. The positron spectrum and fraction measured below a few GeV are consistently reproduced only withinmore » low reacceleration models. We also constrain the scale-height z{sub t} of the cosmic-ray distribution using three independent (and, in two cases, original) arguments, showing that values of z{sub t} ∼< 2kpc are excluded. This result may have strong implications for particle dark matter searches.« less

Positron Radiography of Ignition-Relevant ICF Capsules

NASA Astrophysics Data System (ADS)

Williams, Jackson; Chen, Hui; Field, John; Landen, Nino; Strozzi, David

2017-10-01

X-ray and neutron radiography are currently used to infer residual ICF shell and fuel asymmetries and areal density non-uniformities near and at peak compression that can impede ignition. Charged particles offer an alternative probe source that, in principle, are capable of radiographing the shell shape and areal density at arbitrary times, even in the presence of large x-ray self-emission. Laser-generated positrons are evaluated as a source to radiograph ICF capsules where current ultraintense laser facilities are capable of producing 2 ×1012 relativistic positrons in a narrow energy bandwidth and short duration. Monte Carlo simulations suggest that both the areal density and shell radius can be reconstructed for ignition-relevant capsules conditions between 0.002-2 g/cm2, and that this technique might be better suited to direct-drive. This work was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344 and funded by the LDRD Program under project tracking code 17-ERD-010.

SLC30A9 mutation affecting intracellular zinc homeostasis causes a novel cerebro-renal syndrome

PubMed Central

Perez, Yonatan; Shorer, Zamir; Liani-Leibson, Keren; Chabosseau, Pauline; Kadir, Rotem; Volodarsky, Michael; Halperin, Daniel; Barber-Zucker, Shiran; Shalev, Hanna; Schreiber, Ruth; Gradstein, Libe; Gurevich, Evgenia; Zarivach, Raz; Rutter, Guy A.; Landau, Daniel

2017-01-01

Abstract A novel autosomal recessive cerebro-renal syndrome was identified in consanguineous Bedouin kindred: neurological deterioration was evident as of early age, progressing into severe intellectual disability, profound ataxia, camptocormia and oculomotor apraxia. Brain MRI was normal. Four of the six affected individuals also had early-onset nephropathy with features of tubulo-interstitial nephritis, hypertension and tendency for hyperkalemia, though none had rapid deterioration of renal function. Genome wide linkage analysis identified an ∼18 Mb disease-associated locus on chromosome 4 (maximal logarithm of odds score 4.4 at D4S2971; θ = 0). Whole exome sequencing identified a single mutation in SLC30A9 within this locus, segregating as expected within the kindred and not found in a homozygous state in 300 Bedouin controls. We showed that SLC30A9 (solute carrier family 30 member 9; also known as ZnT-9) is ubiquitously expressed with high levels in cerebellum, skeletal muscle, thymus and kidney. Confocal analysis of SH-SY5Y cells overexpressing SLC30A9 fused to enhanced green fluorescent protein demonstrated vesicular cytosolic localization associated with the endoplasmic reticulum, not co-localizing with endosomal or Golgi markers. SLC30A9 encodes a putative zinc transporter (by similarity) previously associated with Wnt signalling. However, using dual-luciferase reporter assay in SH-SY5Y cells we showed that Wnt signalling was not affected by the mutation. Based on protein modelling, the identified mutation is expected to affect SLC30A9’s highly conserved cation efflux domain, putatively disrupting its transmembrane helix structure. Cytosolic Zn2+ measurements in HEK293 cells overexpressing wild-type and mutant SLC30A9 showed lower zinc concentration within mutant rather than wild-type SLC30A9 cells. This suggests that SLC30A9 has zinc transport properties affecting intracellular zinc homeostasis, and that the molecular mechanism of the disease is through defective function of this novel activity of SLC30A9 rather than by a defect in its previously described role in transcriptional activation of Wnt signalling. PMID:28334855

Human SLC4A11 Is a Novel NH3/H+ Co-transporter*

PubMed Central

Zhang, Wenlin; Ogando, Diego G.; Bonanno, Joseph A.; Obukhov, Alexander G.

2015-01-01

SLC4A11 has been proposed to be an electrogenic membrane transporter, permeable to Na+, H+ (OH−), bicarbonate, borate, and NH4+. Recent studies indicate, however, that neither bicarbonate or borate is a substrate. Here, we examined potential NH4+, Na+, and H+ contributions to electrogenic ion transport through SLC4A11 stably expressed in Na+/H+ exchanger-deficient PS120 fibroblasts. Inward currents observed during exposure to NH4Cl were determined by the [NH3]o, not [NH4+]o, and current amplitudes varied with the [H+] gradient. These currents were relatively unaffected by removal of Na+, K+, or Cl− from the bath but could be reduced by inclusion of NH4Cl in the pipette solution. Bath pH changes alone did not generate significant currents through SLC4A11, except immediately following exposure to NH4Cl. Reversal potential shifts in response to changing [NH3]o and pHo suggested an NH3/H+-coupled transport mode for SLC4A11. Proton flux through SLC4A11 in the absence of ammonia was relatively small, suggesting that ammonia transport is of more physiological relevance. Methylammonia produced currents similar to NH3 but with reduced amplitude. Estimated stoichiometry of SLC4A11 transport was 1:2 (NH3/H+). NH3-dependent currents were insensitive to 10 μm ethyl-isopropyl amiloride or 100 μm 4,4′- diisothiocyanatostilbene-2,2′-disulfonic acid. We propose that SLC4A11 is an NH3/2H+ co-transporter exhibiting unique characteristics. PMID:26018076

Genes and proteins of urea transporters.

PubMed

Sands, Jeff M; Blount, Mitsi A

2014-01-01

A urea transporter protein in the kidney was first proposed in 1987. The first urea transporter cDNA was cloned in 1993. The SLC14a urea transporter family contains two major subgroups: SLC14a1, the UT-B urea transporter originally isolated from erythrocytes; and SLC14a2, the UT-A group originally isolated from kidney inner medulla. Slc14a1, the human UT-B gene, arises from a single locus located on chromosome 18q12.1-q21.1, which is located close to Slc14a2. Slc14a1 includes 11 exons, with the coding region extending from exon 4 to exon 11, and is approximately 30 kb in length. The Slc14a2 gene is a very large gene with 24 exons, is approximately 300 kb in length, and encodes 6 different isoforms. Slc14a2 contains two promoter elements: promoter I is located in the typical position, upstream of exon 1, and drives the transcription of UT-A1, UT-A1b, UT-A3, UT-A3b, and UT-A4; while promoter II is located within intron 12 and drives the transcription of UT-A2 and UT-A2b. UT-A1 and UT-A3 are located in the inner medullary collecting duct, UT-A2 in the thin descending limb and liver, UT-A5 in testis, UT-A6 in colon, UT-B1 primarily in descending vasa recta and erythrocytes, and UT-B2 in rumen.

Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease.

PubMed

Johnson, Janel O; Gibbs, J Raphael; Megarbane, Andre; Urtizberea, J Andoni; Hernandez, Dena G; Foley, A Reghan; Arepalli, Sampath; Pandraud, Amelie; Simón-Sánchez, Javier; Clayton, Peter; Reilly, Mary M; Muntoni, Francesco; Abramzon, Yevgeniya; Houlden, Henry; Singleton, Andrew B

2012-09-01

Brown-Vialetto-Van Laere syndrome was first described in 1894 as a rare neurodegenerative disorder characterized by progressive sensorineural deafness in combination with childhood amyotrophic lateral sclerosis. Mutations in the gene, SLC52A3 (formerly C20orf54), one of three known riboflavin transporter genes, have recently been shown to underlie a number of severe cases of Brown-Vialetto-Van Laere syndrome; however, cases and families with this disease exist that do not appear to be caused by SLC52A3 mutations. We used a combination of linkage and exome sequencing to identify the disease causing mutation in an extended Lebanese Brown-Vialetto-Van Laere kindred, whose affected members were negative for SLC52A3 mutations. We identified a novel mutation in a second member of the riboflavin transporter gene family (gene symbol: SLC52A2) as the cause of disease in this family. The same mutation was identified in one additional subject, from 44 screened. Within this group of 44 patients, we also identified two additional cases with SLC52A3 mutations, but none with mutations in the remaining member of this gene family, SLC52A1. We believe this strongly supports the notion that defective riboflavin transport plays an important role in Brown-Vialetto-Van Laere syndrome. Initial work has indicated that patients with SLC52A3 defects respond to riboflavin treatment clinically and biochemically. Clearly, this makes an excellent candidate therapy for the SLC52A2 mutation-positive patients identified here. Initial riboflavin treatment of one of these patients shows promising results.

Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease

PubMed Central

Johnson, Janel O.; Gibbs, J. Raphael; Megarbane, Andre; Urtizberea, J. Andoni; Hernandez, Dena G.; Foley, A. Reghan; Arepalli, Sampath; Pandraud, Amelie; Simón-Sánchez, Javier; Clayton, Peter; Reilly, Mary M.; Muntoni, Francesco; Abramzon, Yevgeniya; Houlden, Henry

2012-01-01

Brown–Vialetto–Van Laere syndrome was first described in 1894 as a rare neurodegenerative disorder characterized by progressive sensorineural deafness in combination with childhood amyotrophic lateral sclerosis. Mutations in the gene, SLC52A3 (formerly C20orf54), one of three known riboflavin transporter genes, have recently been shown to underlie a number of severe cases of Brown–Vialetto–Van Laere syndrome; however, cases and families with this disease exist that do not appear to be caused by SLC52A3 mutations. We used a combination of linkage and exome sequencing to identify the disease causing mutation in an extended Lebanese Brown–Vialetto–Van Laere kindred, whose affected members were negative for SLC52A3 mutations. We identified a novel mutation in a second member of the riboflavin transporter gene family (gene symbol: SLC52A2) as the cause of disease in this family. The same mutation was identified in one additional subject, from 44 screened. Within this group of 44 patients, we also identified two additional cases with SLC52A3 mutations, but none with mutations in the remaining member of this gene family, SLC52A1. We believe this strongly supports the notion that defective riboflavin transport plays an important role in Brown–Vialetto–Van Laere syndrome. Initial work has indicated that patients with SLC52A3 defects respond to riboflavin treatment clinically and biochemically. Clearly, this makes an excellent candidate therapy for the SLC52A2 mutation-positive patients identified here. Initial riboflavin treatment of one of these patients shows promising results. PMID:22740598

Contribution from individual nearby sources to the spectrum of high-energy cosmic-ray electrons

NASA Astrophysics Data System (ADS)

Sedrati, R.; Attallah, R.

2014-04-01

In the last few years, very important data on high-energy cosmic-ray electrons and positrons from high-precision space-born and ground-based experiments have attracted a great deal of interest. These particles represent a unique probe for studying local comic-ray accelerators because they lose energy very rapidly. These energy losses reduce the lifetime so drastically that high-energy cosmic-ray electrons can attain the Earth only from rather local astrophysical sources. This work aims at calculating, by means of Monte Carlo simulation, the contribution from some known nearby astrophysical sources to the cosmic-ray electron/positron spectra at high energy (≥ 10 GeV). The background to the electron energy spectrum from distant sources is determined with the help of the GALPROP code. The obtained numerical results are compared with a set of experimental data.

Sodium bicarbonate cotransporter NBCe2 gene variants increase sodium and bicarbonate transport in human renal proximal tubule cells.

PubMed

Gildea, John J; Xu, Peng; Kemp, Brandon A; Carlson, Julia M; Tran, Hanh T; Bigler Wang, Dora; Langouët-Astrié, Christophe J; McGrath, Helen E; Carey, Robert M; Jose, Pedro A; Felder, Robin A

2018-01-01

Salt sensitivity of blood pressure affects >30% of the hypertensive and >15% of the normotensive population. Variants of the electrogenic sodium bicarbonate cotransporter NBCe2 gene, SLC4A5, are associated with increased blood pressure in several ethnic groups. SLC4A5 variants are also highly associated with salt sensitivity, independent of hypertension. However, little is known about how NBCe2 contributes to salt sensitivity, although NBCe2 regulates renal tubular sodium bicarbonate transport. We hypothesized that SLC4A5 rs10177833 and rs7571842 increase NBCe2 expression and human renal proximal tubule cell (hRPTC) sodium transport and may be a cause of salt sensitivity of blood pressure. To characterize the hRPTC ion transport of wild-type (WT) and homozygous variants (HV) of SLC4A5. The expressions of NBCe2 mRNA and protein were not different between hRPTCs carrying WT or HV SLC4A5 before or after dopaminergic or angiotensin (II and III) stimulation. However, luminal to basolateral sodium transport, NHE3 protein, and Cl-/HCO3- exchanger activity in hRPTCs were higher in HV than WT SLC4A5. Increasing intracellular sodium enhanced the apical location of NBCe2 in HV hRPTCs (4.24±0.35% to 11.06±1.72% (P<0.05, N = 3, 2-way ANOVA, Holm-Sidak test)) as determined by Total Internal Reflection Fluorescence Microscopy (TIRFM). In hRPTCs isolated from kidney tissue, increasing intracellular sodium enhanced bicarbonate-dependent pH recovery rate and increased NBCe2 mRNA and protein expressions to a greater extent in HV than WT SLC4A5 (+38.00±6.23% vs HV normal salt (P<0.01, N = 4, 2-way ANOVA, Holm-Sidak test)). In hRPTCs isolated from freshly voided urine, bicarbonate-dependent pH recovery was also faster in those from salt-sensitive and carriers of HV SLC4A5 than from salt-resistant and carriers of WT SLC4A5. The faster NBCe2-specific bicarbonate-dependent pH recovery rate in HV SCL4A5 was normalized by SLC4A5- but not SLC4A4-shRNA. The binding of purified hepatocyte nuclear factor type 4A (HNF4A) to DNA was increased in hRPTCs carrying HV SLC4A5 rs7571842 but not rs10177833. The faster NBCe2-specific bicarbonate-dependent pH recovery rate in HV SCL4A5 was abolished by HNF4A antagonists. NBCe2 activity is stimulated by an increase in intracellular sodium and is hyper-responsive in hRPTCs carrying HV SLC4A5 rs7571842 through an aberrant HNF4A-mediated mechanism.

A SLC4 family bicarbonate transporter is critical for intracellular pH regulation and biomineralization in sea urchin embryos.

PubMed

Hu, Marian Y; Yan, Jia-Jiun; Petersen, Inga; Himmerkus, Nina; Bleich, Markus; Stumpp, Meike

2018-05-01

Efficient pH regulation is a fundamental requisite of all calcifying systems in animals and plants but with the underlying pH regulatory mechanisms remaining largely unknown. Using the sea urchin larva, this work identified the SLC4 HCO 3 - transporter family member SpSlc4a10 to be critically involved in the formation of an elaborate calcitic endoskeleton. SpSlc4a10 is specifically expressed by calcifying primary mesenchyme cells with peak expression during de novo formation of the skeleton. Knock-down of SpSlc4a10 led to pH regulatory defects accompanied by decreased calcification rates and skeleton deformations. Reductions in seawater pH, resembling ocean acidification scenarios, led to an increase in SpSlc4a10 expression suggesting a compensatory mechanism in place to maintain calcification rates. We propose a first pH regulatory and HCO 3 - concentrating mechanism that is fundamentally linked to the biological precipitation of CaCO 3 . This knowledge will help understanding biomineralization strategies in animals and their interaction with a changing environment. © 2018, Hu et al.

A SLC4 family bicarbonate transporter is critical for intracellular pH regulation and biomineralization in sea urchin embryos

PubMed Central

Yan, Jia-Jiun; Petersen, Inga; Himmerkus, Nina; Bleich, Markus; Stumpp, Meike

2018-01-01

Efficient pH regulation is a fundamental requisite of all calcifying systems in animals and plants but with the underlying pH regulatory mechanisms remaining largely unknown. Using the sea urchin larva, this work identified the SLC4 HCO3- transporter family member SpSlc4a10 to be critically involved in the formation of an elaborate calcitic endoskeleton. SpSlc4a10 is specifically expressed by calcifying primary mesenchyme cells with peak expression during de novo formation of the skeleton. Knock-down of SpSlc4a10 led to pH regulatory defects accompanied by decreased calcification rates and skeleton deformations. Reductions in seawater pH, resembling ocean acidification scenarios, led to an increase in SpSlc4a10 expression suggesting a compensatory mechanism in place to maintain calcification rates. We propose a first pH regulatory and HCO3- concentrating mechanism that is fundamentally linked to the biological precipitation of CaCO3. This knowledge will help understanding biomineralization strategies in animals and their interaction with a changing environment. PMID:29714685

SLC: The End Game

DOE Office of Scientific and Technical Information (OSTI.GOV)

Raimondi, Pantaleo

The design of the Stanford Linear Collider (SLC) called for a beam intensity far beyond what was practically achievable. This was due to intrinsic limitations in many subsystems and to a lack of understanding of the new physics of linear colliders. Real progress in improving the SLC performance came from precision, non-invasive diagnostics to measure and monitor the beams and from new techniques to control the emittance dilution and optimize the beams. A major contribution to the success of the last 1997-98 SLC run came from several innovative ideas for improving the performance of the Final Focus (FF). This papermore » describes some of the problems encountered and techniques used to overcome them. Building on the SLC experience, we will also present a new approach to the FF design for future high energy linear colliders.« less

Exonal deletion of SLC24A4 causes hypomaturation amelogenesis imperfecta.

PubMed

Seymen, F; Lee, K-E; Tran Le, C G; Yildirim, M; Gencay, K; Lee, Z H; Kim, J-W

2014-04-01

Amelogenesis imperfecta is a heterogeneous group of genetic conditions affecting enamel formation. Recently, mutations in solute carrier family 24 member 4 (SLC24A4) have been identified to cause autosomal recessive hypomaturation amelogenesis imperfecta. We recruited a consanguineous family with hypomaturation amelogenesis imperfecta with generalized brown discoloration. Sequencing of the candidate genes identified a 10-kb deletion, including exons 15, 16, and most of the last exon of the SLC24A4 gene. Interestingly, this deletion was caused by homologous recombination between two 354-bp-long homologous sequences located in intron 14 and the 3' UTR. This is the first report of exonal deletion in SLC24A4 providing confirmatory evidence that the function of SLC24A4 in calcium transport has a crucial role in the maturation stage of amelogenesis.

High resolution positron annihilation induced Auger electron spectroscopy of the CuM 2,3VV-transition and of Cu sub-monolayers on Pd and Fe

NASA Astrophysics Data System (ADS)

Mayer, J.; Hugenschmidt, C.; Schreckenbach, K.

2010-09-01

We present a high resolution positron annihilation induced Auger Electron Spectroscopy (PAES) of the CuM 2,3VV-transition with the unprecedented energy resolution of Δ/EE <1%. This energy resolution and the highly intense positron source NEPOMUC enabled us to resolve the double peak structure with PAES for the first time within a measurement time of only 5.5 h. In addition, sub-monolayers of Cu were deposited on Fe- and Pd-samples in order to investigate the surface selectivity of PAES in comparison with EAES. The extremely high surface selectivity of PAES due to the different positron affinity of Cu and Fe lead to the result that with only 0.96 monolayer of Cu on Fe more than 55% of the emitted Auger electrons stem from Cu, whereas with EAES the Cu Auger fraction amounted to less than 6%.

Positron annihilation lifetime spectroscopy (PALS) study of the as prepared and calcined MFI zeolites

NASA Astrophysics Data System (ADS)

Bosnar, Sanja; Vrankić, Martina; Bosnar, Damir; Ren, Nan; Šarić, Ankica

2017-11-01

The synthesis of high silica zeolites in many cases implies the usage of organic structural direction agents (SDA). However, to manifest their functionalities, the SDA occluded inside the channels of the as-synthesized structure should be removed, usually by a high temperature treatment (calcination). In this paper, the positron annihilation lifetime spectroscopy (PALS) was used to monitor the development of accessible spaces, their sizes and distributions in MFI zeolites, ZSM-5 and silicalite-1 in order to give an additional insight in the process of the SDA removal. For that purpose, a conventional PALS setup with 22Na positron source was applied. It was established that there is a pronounced difference between positron annihilation data for these two zeolites of the same structural type. The samples were additionally analysed by X-ray powder diffraction at room temperature with a crystal structure refinement and thermogravimetry.

Fructose Synthesis and Transport at the Uterine-Placental Interface of Pigs: Cell-Specific Localization of SLC2A5, SLC2A8, and Components of the Polyol Pathway.

PubMed

Steinhauser, Chelsie B; Landers, McKinsey; Myatt, Louise; Burghardt, Robert C; Vallet, Jeffrey L; Bazer, Fuller W; Johnson, Greg A

2016-11-01

The fetal fluids and uterine flushings of pigs contain higher concentrations of fructose than glucose, but fructose is not detected in maternal blood. Fructose can be synthesized from glucose via enzymes of the polyol pathway, aldose reductase (AKR1B1) and sorbitol dehydrogenase (SORD), transported across cell membranes by solute carriers SLC2A5 and SLC2A8, and converted to fructose-1-phosphate by ketohexokinase (KHK). SLC2A8, SLC2A5, AKR1B1, SORD, and KHK mRNAs and proteins were analyzed using quantitative PCR and immunohistochemistry or in situ hybridization in endometria and placentae of cyclic and pregnant gilts, cyclic gilts injected with estrogen, and ovariectomized gilts injected with progesterone. Progesterone up-regulated SLC2A8 protein in uterine luminal (LE) and glandular epithelia during the peri-implantation period, and expression became exclusively placental, chorion and blood vessels, after Day 30. P4 up-regulated SLC2A5 mRNA in uterine LE and glandular epithelia after implantation, and the chorion expressed SLC2A5 between Days 30 and 85. AKR1B1 and SORD proteins localized to uterine LE during the peri-implantation period, but expression switched to chorion by Day 20 and was maintained through Day 85. Uterine expression of AKR1B1 mRNA was down-regulated by estrogen. KHK protein localized to trophectoderm/chorion throughout gestation. These results provide evidence that components for the conversion of glucose to fructose and for fructose transport are present at the uterine-placental interface of pigs. The shift in expression from LE to chorion during pregnancy suggests free-floating conceptuses are supported by fructose synthesized by the uterus, but after implantation, the chorion becomes self-sufficient for fructose synthesis and transport. © 2016 by the Society for the Study of Reproduction, Inc.

SLC6A1 Mutation and Ketogenic Diet in Epilepsy With Myoclonic-Atonic Seizures.

PubMed

Palmer, Samantha; Towne, Meghan C; Pearl, Phillip L; Pelletier, Renee C; Genetti, Casie A; Shi, Jiahai; Beggs, Alan H; Agrawal, Pankaj B; Brownstein, Catherine A

2016-11-01

Epilepsy with myoclonic-atonic seizures, also known as myoclonic-astatic epilepsy or Doose syndrome, has been recently linked to variants in the SLC6A1 gene. Epilepsy with myoclonic-atonic seizures is often refractory to antiepileptic drugs, and the ketogenic diet is known for treating medically intractable seizures, although the mechanism of action is largely unknown. We report a novel SLC6A1 variant in a patient with epilepsy with myoclonic-atonic seizures, analyze its effects, and suggest a mechanism of action for the ketogenic diet. We describe a ten-year-old girl with epilepsy with myoclonic-atonic seizures and a de novo SLC6A1 mutation who responded well to the ketogenic diet. She carried a c.491G>A mutation predicted to cause p.Cys164Tyr amino acid change, which was identified using whole exome sequencing and confirmed by Sanger sequencing. High-resolution structural modeling was used to analyze the likely effects of the mutation. The SLC6A1 gene encodes a transporter that removes gamma-aminobutyric acid from the synaptic cleft. Mutations in SLC6A1 are known to disrupt the gamma-aminobutyric acid transporter protein 1, affecting gamma-aminobutyric acid levels and causing seizures. The p.Cys164Tyr variant found in our study has not been previously reported, expanding on the variants linked to epilepsy with myoclonic-atonic seizures. A 10-year-old girl with a novel SLC6A1 mutation and epilepsy with myoclonic-atonic seizures had an excellent clinical response to the ketogenic diet. An effect of the diet on gamma-aminobutyric acid reuptake mediated by gamma-aminobutyric acid transporter protein 1 is suggested. A personalized approach to epilepsy with myoclonic-atonic seizures patients carrying SLC6A1 mutation and a relationship between epilepsy with myoclonic-atonic seizures due to SLC6A1 mutations, GABAergic drugs, and the ketogenic diet warrants further exploration. Copyright © 2016 Elsevier Inc. All rights reserved.

Complex analysis of urate transporters SLC2A9, SLC22A12 and functional characterization of non-synonymous allelic variants of GLUT9 in the Czech population: no evidence of effect on hyperuricemia and gout.

PubMed

Hurba, Olha; Mancikova, Andrea; Krylov, Vladimir; Pavlikova, Marketa; Pavelka, Karel; Stibůrková, Blanka

2014-01-01

Using European descent Czech populations, we performed a study of SLC2A9 and SLC22A12 genes previously identified as being associated with serum uric acid concentrations and gout. This is the first study of the impact of non-synonymous allelic variants on the function of GLUT9 except for patients suffering from renal hypouricemia type 2. The cohort consisted of 250 individuals (150 controls, 54 nonspecific hyperuricemics and 46 primary gout and/or hyperuricemia subjects). We analyzed 13 exons of SLC2A9 (GLUT9 variant 1 and GLUT9 variant 2) and 10 exons of SLC22A12 by PCR amplification and sequenced directly. Allelic variants were prepared and their urate uptake and subcellular localization were studied by Xenopus oocytes expression system. The functional studies were analyzed using the non-parametric Wilcoxon and Kruskall-Wallis tests; the association study used the Fisher exact test and linear regression approach. We identified a total of 52 sequence variants (12 unpublished). Eight non-synonymous allelic variants were found only in SLC2A9: rs6820230, rs2276961, rs144196049, rs112404957, rs73225891, rs16890979, rs3733591 and rs2280205. None of these variants showed any significant difference in the expression of GLUT9 and in urate transport. In the association study, eight variants showed a possible association with hyperuricemia. However, seven of these were in introns and the one exon located variant, rs7932775, did not show a statistically significant association with serum uric acid concentration. Our results did not confirm any effect of SLC22A12 and SLC2A9 variants on serum uric acid concentration. Our complex approach using association analysis together with functional and immunohistochemical characterization of non-synonymous allelic variants did not show any influence on expression, subcellular localization and urate uptake of GLUT9.

slc7a6os gene plays a critical role in defined areas of the developing CNS in zebrafish.

PubMed

Benini, Anna; Cignarella, Francesca; Calvarini, Laura; Mantovanelli, Silvia; Giacopuzzi, Edoardo; Zizioli, Daniela; Borsani, Giuseppe

2015-01-01

The aim of this study is to shed light on the functional role of slc7a6os, a gene highly conserved in vertebrates. The Danio rerio slc7a6os gene encodes a protein of 326 amino acids with 46% identity to human SLC7A6OS and 14% to Saccharomyces cerevisiae polypeptide Iwr1. Yeast Iwr1 specifically binds RNA pol II, interacts with the basal transcription machinery and regulates the transcription of specific genes. In this study we investigated for the first time the biological role of SLC7A6OS in vertebrates. Zebrafish slc7a6os is a maternal gene that is expressed throughout development, with a prevalent localization in the developing central nervous system (CNS). The gene is also expressed, although at different levels, in various tissues of the adult fish. To determine the functional role of slc7a6os during zebrafish development, we knocked-down the gene by injecting a splice-blocking morpholino. At 24 hpf morphants show morphological defects in the CNS, particularly the interface between hindbrain and midbrain is not well-defined. At 28 hpf the morpholino injected embryos present an altered somite morphology and appear partially or completely immotile. At this stage the midbrain, hindbrain and cerebellum are compromised and not well defined compared with control embryos. The observed alterations persist at later developmental stages. Consistently, the expression pattern of two markers specifically expressed in the developing CNS, pax2a and neurod, is significantly altered in morphants. The co-injection of embryos with synthetic slc7a6os mRNA, rescues the morphant phenotype and restores the wild type expression pattern of pax2a and neurod. Our data suggest that slc7a6os might play a critical role in defined areas of the developing CNS in vertebrates, probably by regulating the expression of key genes.

slc7a6os Gene Plays a Critical Role in Defined Areas of the Developing CNS in Zebrafish

PubMed Central

Benini, Anna; Cignarella, Francesca; Calvarini, Laura; Mantovanelli, Silvia; Giacopuzzi, Edoardo; Zizioli, Daniela; Borsani, Giuseppe

2015-01-01

The aim of this study is to shed light on the functional role of slc7a6os, a gene highly conserved in vertebrates. The Danio rerio slc7a6os gene encodes a protein of 326 amino acids with 46% identity to human SLC7A6OS and 14% to Saccharomyces cerevisiae polypeptide Iwr1. Yeast Iwr1 specifically binds RNA pol II, interacts with the basal transcription machinery and regulates the transcription of specific genes. In this study we investigated for the first time the biological role of SLC7A6OS in vertebrates. Zebrafish slc7a6os is a maternal gene that is expressed throughout development, with a prevalent localization in the developing central nervous system (CNS). The gene is also expressed, although at different levels, in various tissues of the adult fish. To determine the functional role of slc7a6os during zebrafish development, we knocked-down the gene by injecting a splice-blocking morpholino. At 24 hpf morphants show morphological defects in the CNS, particularly the interface between hindbrain and midbrain is not well-defined. At 28 hpf the morpholino injected embryos present an altered somite morphology and appear partially or completely immotile. At this stage the midbrain, hindbrain and cerebellum are compromised and not well defined compared with control embryos. The observed alterations persist at later developmental stages. Consistently, the expression pattern of two markers specifically expressed in the developing CNS, pax2a and neurod, is significantly altered in morphants. The co-injection of embryos with synthetic slc7a6os mRNA, rescues the morphant phenotype and restores the wild type expression pattern of pax2a and neurod. Our data suggest that slc7a6os might play a critical role in defined areas of the developing CNS in vertebrates, probably by regulating the expression of key genes. PMID:25803583

Inhibition of Intestinal Bile Acid Transporter Slc10a2 Improves Triglyceride Metabolism and Normalizes Elevated Plasma Glucose Levels in Mice

PubMed Central

Snaith, Michael; Lindmark, Helena; Lundberg, Johanna; Östlund-Lindqvist, Ann-Margret; Angelin, Bo; Rudling, Mats

2012-01-01

Interruption of the enterohepatic circulation of bile acids increases cholesterol catabolism, thereby stimulating hepatic cholesterol synthesis from acetate. We hypothesized that such treatment should lower the hepatic acetate pool which may alter triglyceride and glucose metabolism. We explored this using mice deficient of the ileal sodium-dependent BA transporter (Slc10a2) and ob/ob mice treated with a specific inhibitor of Slc10a2. Plasma TG levels were reduced in Slc10a2-deficient mice, and when challenged with a sucrose-rich diet, they displayed a reduced response in hepatic TG production as observed from the mRNA levels of several key enzymes in fatty acid synthesis. This effect was paralleled by a diminished induction of mature sterol regulatory element-binding protein 1c (Srebp1c). Unexpectedly, the SR-diet induced intestinal fibroblast growth factor (FGF) 15 mRNA and normalized bile acid synthesis in Slc10a2−/− mice. Pharmacologic inhibition of Slc10a2 in diabetic ob/ob mice reduced serum glucose, insulin and TGs, as well as hepatic mRNA levels of Srebp1c and its target genes. These responses are contrary to those reported following treatment of mice with a bile acid binding resin. Moreover, when key metabolic signal transduction pathways in the liver were investigated, those of Mek1/2 - Erk1/2 and Akt were blunted after treatment of ob/ob mice with the Slc10a2 inhibitor. It is concluded that abrogation of Slc10a2 reduces hepatic Srebp1c activity and serum TGs, and in the diabetic ob/ob model it also reduces glucose and insulin levels. Hence, targeting of Slc10a2 may be a promising strategy to treat hypertriglyceridemia and diabetes. PMID:22662222

Molecular Analysis of Congenital Hypothyroidism in Saudi Arabia: SLC26A7 Mutation Is a Novel Defect in Thyroid Dyshormonogenesis.

PubMed

Zou, Minjing; Alzahrani, Ali S; Al-Odaib, Ali; Alqahtani, Mohammad A; Babiker, Omer; Al-Rijjal, Roua A; BinEssa, Huda A; Kattan, Walaa E; Al-Enezi, Anwar F; Al Qarni, Ali; Al-Faham, Manar S A; Baitei, Essa Y; Alsagheir, Afaf; Meyer, Brian F; Shi, Yufei

2018-05-01

Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder, affecting one in 3000 to 4000 newborns. Since the introduction of a newborn screening program in 1988, more than 300 cases have been identified. The underlying genetic defects have not been systematically studied. To identify the mutation spectrum of CH-causing genes. Fifty-five patients from 47 families were studied by next-generation exome sequencing. Mutations were identified in 52.7% of patients (29 of 55) in the following 11 genes: TG, TPO, DUOX2, SLC26A4, SLC26A7, TSHB, TSHR, NKX2-1, PAX8, CDCA8, and HOXB3. Among 30 patients with thyroid dyshormonogenesis, biallelic TG mutations were found in 12 patients (40%), followed by biallelic mutations in TPO (6.7%), SLC26A7 (6.7%), and DUOX2 (3.3%). Monoallelic SLC26A4 mutations were found in two patients, one of them coexisting with two tandem biallelic deletions in SLC26A7. In 25 patients with thyroid dysgenesis, biallelic mutations in TSHR were found in six patients (24%). Biallelic mutations in TSHB, PAX 8, NKX2-1, or HOXB3 were found once in four different patients. A monoallelic CDCA8 mutation was found in one patient. Most mutations were novel, including three TG, two TSHR, and one each in DUOX2, TPO, SLC26A7, TSHB, NKX2-1, PAX8, CDCA8, and HOXB3. SLC26A7 and HOXB3 were novel genes associated with thyroid dyshormonogenesis and dysgenesis, respectively. TG and TSHR mutations are the most common genetic defects in Saudi patients with CH. The prevalence of other disease-causing mutations is low, reflecting the consanguineous nature of the population. SLC26A7 mutations appear to be associated with thyroid dyshormonogenesis.

Cation-Coupled Bicarbonate Transporters

PubMed Central

Aalkjaer, Christian; Boedtkjer, Ebbe; Choi, Inyeong; Lee, Soojung

2016-01-01

Cation-coupled HCO3− transport was initially identified in the mid-1970s when pioneering studies showed that acid extrusion from cells is stimulated by CO2/HCO3− and associated with Na+ and Cl− movement. The first Na+-coupled bicarbonate transporter (NCBT) was expression-cloned in the late 1990s. There are currently five mammalian NCBTs in the SLC4-family: the electrogenic Na,HCO3-cotransporters NBCe1 and NBCe2 (SLC4A4 and SLC4A5 gene products); the electroneutral Na,HCO3-cotransporter NBCn1 (SLC4A7 gene product); the Na+-driven Cl,HCO3-exchanger NDCBE (SLC4A8 gene product); and NBCn2/NCBE (SLC4A10 gene product), which has been characterized as an electroneutral Na,HCO3-cotransporter or a Na+-driven Cl,HCO3-exchanger. Despite the similarity in amino acid sequence and predicted structure among the NCBTs of the SLC4-family, they exhibit distinct differences in ion dependency, transport function, pharmacological properties, and interactions with other proteins. In epithelia, NCBTs are involved in transcellular movement of acid-base equivalents and intracellular pH control. In nonepithelial tissues, NCBTs contribute to intracellular pH regulation; and hence, they are crucial for diverse tissue functions including neuronal discharge, sensory neuron development, performance of the heart, and vascular tone regulation. The function and expression levels of the NCBTs are generally sensitive to intracellular and systemic pH. Animal models have revealed pathophysiological roles of the transporters in disease states including metabolic acidosis, hypertension, visual defects, and epileptic seizures. Studies are being conducted to understand the physiological consequences of genetic polymorphisms in the SLC4-members, which are associated with cancer, hypertension, and drug addiction. Here, we describe the current knowledge regarding the function, structure, and regulation of the mammalian cation-coupled HCO3− transporters of the SLC4-family. PMID:25428855

Sulfate transporters involved in sulfate secretion in the kidney are localized in the renal proximal tubule II of the elephant fish (Callorhinchus milii)

PubMed Central

Kato, Akira; Watanabe, Taro; Takagi, Wataru; Romero, Michael F.; Bell, Justin D.; Toop, Tes; Donald, John A.; Hyodo, Susumu

2016-01-01

Most vertebrates, including cartilaginous fishes, maintain their plasma SO42− concentration ([SO42−]) within a narrow range of 0.2–1 mM. As seawater has a [SO42−] about 40 times higher than that of the plasma, SO42− excretion is the major role of kidneys in marine teleost fishes. It has been suggested that cartilaginous fishes also excrete excess SO42− via the kidney. However, little is known about the underlying mechanisms for SO42− transport in cartilaginous fish, largely due to the extraordinarily elaborate four-loop configuration of the nephron, which consists of at least 10 morphologically distinguishable segments. In the present study, we determined cDNA sequences from the kidney of holocephalan elephant fish (Callorhinchus milii) that encoded solute carrier family 26 member 1 (Slc26a1) and member 6 (Slc26a6), which are SO42− transporters that are expressed in mammalian and teleost kidneys. Elephant fish Slc26a1 (cmSlc26a1) and cmSlc26a6 mRNAs were coexpressed in the proximal II (PII) segment of the nephron, which comprises the second loop in the sinus zone. Functional analyses using Xenopus oocytes and the results of immunohistochemistry revealed that cmSlc26a1 is a basolaterally located electroneutral SO42− transporter, while cmSlc26a6 is an apically located, electrogenic Cl−/SO42− exchanger. In addition, we found that both cmSlc26a1 and cmSlc26a6 were abundantly expressed in the kidney of embryos; SO42− was concentrated in a bladder-like structure of elephant fish embryos. Our results demonstrated that the PII segment of the nephron contributes to the secretion of excess SO42− by the kidney of elephant fish. Possible mechanisms for SO42− secretion in the PII segment are discussed. PMID:27122370

Colloid centrifugation of fresh stallion semen before cryopreservation decreased microorganism load of frozen-thawed semen without affecting seminal kinetics.

PubMed

Guimarães, T; Lopes, G; Pinto, M; Silva, E; Miranda, C; Correia, M J; Damásio, L; Thompson, G; Rocha, A

2015-01-15

Freezability of equine semen may be influenced by microorganism population of semen. The objective of this study was to verify the effect of single-layer density gradient centrifugation (SLC) of fresh semen before cryopreservation on semen's microbial load (ML) and sperm cells kinetics after freezing-thawing. For that, one ejaculate was collected from 20 healthy stallions and split into control (C) samples (cryopreserved without previous SLC) and SLC samples (subjected to SLC). Semen cryopreservation was performed according to the same protocol in both groups. Microbial load of each microorganism species and total microbial load (TML) expressed in colony-forming units (CFU/mL) as well as frozen-thawed sperm kinetics were assessed in both groups. Additional analysis of the TML was performed, subdividing the frozen-thawed samples in "suitable" (total motility ≥ 30%) and "unsuitable" (total motility < 30%) semen for freezing programs, and comparing the C and SLC groups within these subpopulations. After thawing, SLC samples had less (P < 0.05) TML (88.65 × 10(2) ± 83.8 × 10(2) CFU/mL) than C samples (155.69 × 10(2) ± 48.85 × 10(2) CFU/mL), mainly due to a reduction of Enterococcus spp. and Bacillus spp. A relationship between post-thaw motility and SLC effect on ML was noted, as only in samples with more than 30% total motility was ML reduced (P < 0.05) by SLC (from 51.33 × 10(2) ± 33.26 × 10(2) CFU/mL to 26.68 × 10(2) ± 12.39 × 10(2) CFU/mL in "suitable" frozen-thawed semen vs. 240.90 × 10(2) ± 498.20 × 10(2) to 139.30 × 10(2) ± 290.30 × 10(2) CFU/mL in "unsuitable" frozen-thawed semen). The effect of SLC on kinetics of frozen-thawed sperm cells was negligible. Copyright © 2015 Elsevier Inc. All rights reserved.

The effects and mechanisms of SLC34A2 on maintaining stem cell-like phenotypes in CD147+ breast cancer stem cells.

PubMed

Lv, Yonggang; Wang, Ting; Fan, Jing; Zhang, Zhenzhen; Zhang, Juliang; Xu, Cheng; Li, Yongping; Zhao, Ge; He, Chenyang; Meng, Huimin; Yang, Hua; Wang, Zhen; Liu, Jiayun; Chen, Jianghao; Wang, Ling

2017-04-01

The cancer stem cell (CSC) hypothesis has gained significant recognition in describing tumorigenesis. Identification of the factors critical to development of breast cancer stem cells (BCSCs) may provide insight into the improvement of effective therapies against breast cancer. In this study, we aim to investigate the biological function of SLC34A2 in affecting the stem cell-like phenotypes in BCSCs and its underlying mechanisms. We demonstrated that CD147 + cells from breast cancer tissue samples and cell lines possessed BCSC-like features, including the ability of self-renewal in vitro, differentiation, and tumorigenic potential in vivo. Flow cytometry analysis showed the presence of a variable fraction of CD147 + cells in 9 of 10 tumor samples. Significantly, SLC34A2 expression in CD147 + BCSCs was enhanced compared with that in differentiated adherent progeny of CD147 + BCSCs and adherently cultured cell line cells. In breast cancer patient cohorts, SLC34A2 expression was found increased in 9 of 10 tumor samples. By using lentiviral-based approach, si-SLC34A2-transduced CD147 + BCSCs showed decreased ability of sphere formation, cell viability in vitro, and tumorigenicity in vivo, which suggested the essential role of SLC34A2 in CD147 + BCSCs. Furthermore, PI3K/AKT pathway and SOX2 were found necessary to maintain the stemness of CD147 + BCSCs by using LY294002 or lentiviral-si-SOX2. Finally, we indicated that SLC34A2 could regulate SOX2 to maintain the stem cell-like features in CD147 + BCSCs through PI3K/AKT pathway. Therefore, our report identifies a novel role of SLC34A2 in BCSCs' state regulation and establishes a rationale for targeting the SLC34A2/PI3K/AKT/SOX2 signaling pathway for breast cancer therapy.

Development and Testing of the Positron Identification By Coincident Annihilation Photons (PICAP) System

NASA Astrophysics Data System (ADS)

Tran, D.; Connell, J. J.; Lopate, C.; Bickford, B.

2014-12-01

Moderate energy positrons (~few to 10 MeV) have seldom been observed in the Heliosphere, due primarily to there not having been dedicated instruments for such measurements. Their detection would have implications in the study of Solar energetic particle events and the transport and modulation of the Solar wind and Galactic cosmic rays. The Positron Identification by Coincident Annihilation Photons (PICAP) system is designed specifically to measure these moderate energy positrons by simultaneously detecting the two 511-keV γ-ray photons that result from a positron stopping in the instrument and the subsequent electron-positron annihilation. This method is also expected to effectively discriminate positrons from protons by measuring the amount of energy deposited in the detectors (dE/dx versus residual energy). PICAP offers a low-mass, low-power option for measuring positrons, electrons, and ions in space. Following Monte Carlo modeling, a PICAP laboratory prototype, adaptable to a space-flight design, was designed, built, and tested. This instrument is comprised of (Si) solid-state detectors, plastic scintillation detectors, and high-Z BGO crystal scintillator suitable for detecting the 511-keV γ rays. The prototype underwent preliminary laboratory testing and calibration using radioactive sources for the purpose of establishing functionality. It has since been exposed to beams of energetic protons (up to ~200 MeV) at Massachusetts General Hospital's Francis H. Burr Proton Beam Therapy Center and positrons and electrons (up to ~10 MeV) at Idaho State University's Idaho Accelerator Center. The goal is to validate modeling and determine the performance of the instrument concept. We will present a summary of modeling calculations and analysis of data taken at the accelerator tests. This work is 95% supported by NASA Grant NNX10AC10G.

NLC Special Projects

Science.gov Websites

Measurement (with NLC RF group) LCLS and related technologies (LCLS work related to NLC work) Collimation Systems (with Beam Delivery group) Combined Laser System (with NLC sources group) Polarized Positron Sources (with NLC sources group) Crab Cavity Phase Control System Timing and RF distribution System (with

High-intensity positron microprobe at the Thomas Jefferson National Accelerator Facility

DOE Office of Scientific and Technical Information (OSTI.GOV)

Golge, S., E-mail: serkan.golge@nasa.gov; Vlahovic, B.; Wojtsekhowski, B.

We present a conceptual design for a novel continuous wave electron-linac based high-intensity high-brightness slow-positron production source with a projected intensity on the order of 10{sup 10 }e{sup +}/s. Reaching this intensity in our design relies on the transport of positrons (T{sub +} below 600 keV) from the electron-positron pair production converter target to a low-radiation and low-temperature area for moderation in a high-efficiency cryogenic rare gas moderator, solid Ne. This design progressed through Monte Carlo optimizations of: electron/positron beam energies and converter target thickness, transport of the e{sup +} beam from the converter to the moderator, extraction of the e{sup +}more » beam from the magnetic channel, a synchronized raster system, and moderator efficiency calculations. For the extraction of e{sup +} from the magnetic channel, a magnetic field terminator plug prototype has been built and experimental results on the effectiveness of the prototype are presented. The dissipation of the heat away from the converter target and radiation protection measures are also discussed.« less

A device to measure the effects of strong magnetic fields on the image resolution of PET scanners

NASA Astrophysics Data System (ADS)

Burdette, D.; Albani, D.; Chesi, E.; Clinthorne, N. H.; Cochran, E.; Honscheid, K.; Huh, S. S.; Kagan, H.; Knopp, M.; Lacasta, C.; Mikuz, M.; Schmalbrock, P.; Studen, A.; Weilhammer, P.

2009-10-01

Very high resolution images can be achieved in small animal PET systems utilizing solid state silicon pad detectors. As these systems approach sub-millimeter resolutions, the range of the positron is becoming the dominant contribution to image blur. The size of the positron range effect depends on the initial positron energy and hence the radioactive tracer used. For higher energy positron emitters, such as Ga68 and Tc94m, which are gaining importance in small animal studies, the width of the annihilation point distribution dominates the spatial resolution. This positron range effect can be reduced by embedding the field of view of the PET scanner in a strong magnetic field. In order to confirm this effect experimentally, we developed a high resolution PET instrument based on silicon pad detectors that can operate in a 7 T magnetic field. In this paper, we describe the instrument and present initial results of a study of the effects of magnetic fields up to 7 T on PET image resolution for Na22 and Ga68 point sources.

Study of PRIMAVERA steel samples by a positron annihilation spectroscopy technique

NASA Astrophysics Data System (ADS)

Grafutin, V.; Ilyukhina, O.; Krsjak, V.; Burcl, R.; Hähner, P.; Erak, D.; Zeman, A.

2010-11-01

In the present article, a positron annihilation spectroscopy investigation of VVER-440/230 weld materials is discussed. Important characteristics of metals such as Fermi energy, concentration of electrons in the conduction band, size and concentration of defects were experimentally determined for three model materials with higher level of copper (0.16 wt.%) and phosphorus (0.027-0.038 wt.%). The impact of neutron irradiation and subsequent annealing on crystal lattice parameters was investigated. The experiments with the angular correlation of positron annihilation radiation (ACAR) complement the published positron annihilation spectroscopy (PAS) studies of the radiation treated VVER materials as well as previous experiments on PRIMAVERA materials. The availability of the experimental reactor to prepare strong 64Cu positron sources provided for unique experimental conditions, such as good resolution of spectra (0.4 mrad) and reasonable short time of measurement (36 h). The present paper aims to contribute to further understanding of RPV (reactor pressure vessel) steels behaviour under irradiation conditions as well as annealing recovery procedures, which have already been applied at several VVER NPP units in Europe.

Controlled Synthesis and Understanding of Growth Mechanism – Parameters for Atmospheric Pressure Hydrothermal Synthesis of Ultrathin Secondary ZnO Nanowires

DOE PAGES

Jiao, Mingzhi; Nguyen, Duc; Nguyen, Van; ...

2015-11-10

We measured luminescence and scintillation in ZnO single crystals by photoluminescence and X-ray-induced luminescence (XRIL). XRIL allowed a direct comparison to be made between the near-band emission (NBE) and trap emissions providing insight into the carrier recombination efficiency in the ZnO crystals. In the origin of green emission, the dominant trap emission in ZnO, was investigated by gamma-induced positron spectroscopy (GIPS) - a unique defect spectroscopy method that enables positron lifetime measurements to be made for a sample without contributions from positron annihilation in the source materials or the surroundings. Moreover, the measurements showed the absence of positron traps inmore » the crystals and yielded a bulk positron lifetime value that is in complete agreement with the predicted theoretical value = thereby confirming the advantage of the GIPS method. By combining scintillation measurements with XRIL, the fast scintillation in ZnO crystals was found to be strongly correlated with the ratio between the defect luminescence and NBE.« less

Positron cooling of antiprotons: precursor of recombination

NASA Astrophysics Data System (ADS)

Tan, J. N.; Estrada, J.; Yesley, P.; Bowden, N.; Oxley, P.; Storry, C.; Wessels, M.; Tan, J.; Gabrielse, G.; Oelert, W.; Scheppers, G.; Gronzonka, D.; Sefsick, T.; Fermann, H.; Zmeskal, H.; Breunlich, W.; Kalinowsky, H.; Wesdorp, C.

2001-05-01

The quest for cold antihydrogen, interrupted with the shut-down of LEAR, resumed with the operation of the newest antiproton decelerator (AD) at CERN.[See G.Gabrielse,Adv. in AMO Physics,vol.45,pp.1-38(2001).] Antiprotons injected into the AD with 2.75 GeV of kinetic energy slow to 5.31 MeV before extraction into the ATRAP apparatus, built for antihydrogen recombination experiments. Antiprotons extracted from the AD and positrons emitted from a 112 mCi ^22Na source are simultaneously accumulated in the ultra-high vacuum and 6 T field of a prototype Penning trap incorporating a miniature rotatable electrode. Preloaded electrons are used to thermalize ~ 10^5 antiprotons with the LHe-cooled trap (4.2K). Over 10^6 positrons/hr can be loaded with a new mechanism involving Rydberg positronium. After accumulation, the positrons are moved through the rotatable electrode into close proximity with the antiprotons to study their interactions. We report the first observation of positron cooling of antiprotons in a nested trap configuration suited for three-body recombination and other mechanisms.

Theoretical Interpretation of Pass 8 Fermi -LAT e + + e - Data

DOE PAGES

Di Mauro, M.; Manconi, S.; Vittino, A.; ...

2017-08-17

The flux of positrons and electrons (e + + e -) has been measured by the Fermi Large Area Telescope (LAT) in the energy range between 7 GeV and 2 TeV. Here, we discuss a number of interpretations of Pass 8 Fermi-LAT e + + e - spectrum, combining electron and positron emission from supernova remnants (SNRs) and pulsar wind nebulae (PWNe), or produced by the collision of cosmic rays (CRs) with the interstellar medium. We also found that the Fermi-LAT spectrum is compatible with the sum of electrons from a smooth SNR population, positrons from cataloged PWNe, and amore » secondary component. If we include in our analysis constraints from the AMS-02 positron spectrum, we obtain a slightly worse fit to the e + + e - Fermi-LAT spectrum, depending on the propagation model. As an additional scenario, we replace the smooth SNR component within 0.7 kpc with the individual sources found in Green's catalog of Galactic SNRs. We find that separate consideration of far and near sources helps to reproduce the e + + e - Fermi-LAT spectrum. However, we show that the fit degrades when the radio constraints on the positron emission from Vela SNR (which is the main contributor at high energies) are taken into account. We find that a break in the power-law injection spectrum at about 100 GeV can also reproduce the measured e + + e -spectrum and, among the CR propagation models that we consider, no reasonable break of the power-law dependence of the diffusion coefficient can modify the electron flux enough to reproduce the observed shape.« less

COSMIC-RAY POSITRONS FROM MILLISECOND PULSARS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Venter, C.; Kopp, A.; Büsching, I.

2015-07-10

Observations by the Fermi Large Area Telescope of γ-ray millisecond pulsar (MSP) light curves imply copious pair production in their magnetospheres, and not exclusively in those of younger pulsars. Such pair cascades may be a primary source of Galactic electrons and positrons, contributing to the observed enhancement in positron flux above ∼10 GeV. Fermi has also uncovered many new MSPs, impacting Galactic stellar population models. We investigate the contribution of Galactic MSPs to the flux of terrestrial cosmic-ray electrons and positrons. Our population synthesis code predicts the source properties of present-day MSPs. We simulate their pair spectra invoking an offset-dipolemore » magnetic field. We also consider positrons and electrons that have been further accelerated to energies of several TeV by strong intrabinary shocks in black widow (BW) and redback (RB) systems. Since MSPs are not surrounded by pulsar wind nebulae or supernova shells, we assume that the pairs freely escape and undergo losses only in the intergalactic medium. We compute the transported pair spectra at Earth, following their diffusion and energy loss through the Galaxy. The predicted particle flux increases for non-zero offsets of the magnetic polar caps. Pair cascades from the magnetospheres of MSPs are only modest contributors around a few tens of GeV to the lepton fluxes measured by the Alpha Magnetic Spectrometer, PAMELA, and Fermi, after which this component cuts off. The contribution by BWs and RBs may, however, reach levels of a few tens of percent at tens of TeV, depending on model parameters.« less

Theoretical Interpretation of Pass 8 Fermi -LAT e + + e - Data

DOE Office of Scientific and Technical Information (OSTI.GOV)

Di Mauro, M.; Manconi, S.; Vittino, A.

The flux of positrons and electrons (e + + e -) has been measured by the Fermi Large Area Telescope (LAT) in the energy range between 7 GeV and 2 TeV. Here, we discuss a number of interpretations of Pass 8 Fermi-LAT e + + e - spectrum, combining electron and positron emission from supernova remnants (SNRs) and pulsar wind nebulae (PWNe), or produced by the collision of cosmic rays (CRs) with the interstellar medium. We also found that the Fermi-LAT spectrum is compatible with the sum of electrons from a smooth SNR population, positrons from cataloged PWNe, and amore » secondary component. If we include in our analysis constraints from the AMS-02 positron spectrum, we obtain a slightly worse fit to the e + + e - Fermi-LAT spectrum, depending on the propagation model. As an additional scenario, we replace the smooth SNR component within 0.7 kpc with the individual sources found in Green's catalog of Galactic SNRs. We find that separate consideration of far and near sources helps to reproduce the e + + e - Fermi-LAT spectrum. However, we show that the fit degrades when the radio constraints on the positron emission from Vela SNR (which is the main contributor at high energies) are taken into account. We find that a break in the power-law injection spectrum at about 100 GeV can also reproduce the measured e + + e -spectrum and, among the CR propagation models that we consider, no reasonable break of the power-law dependence of the diffusion coefficient can modify the electron flux enough to reproduce the observed shape.« less

Light yield and energy resolution studies for SoLid phase 1

NASA Astrophysics Data System (ADS)

Boursette, Delphine; SoLid Collaboration

2017-09-01

The SoLid experiment is searching for sterile neutrinos at a nuclear research reactor. It looks for inverse beta decays (producing a positron and a neutron in delayed coincidence) with a very segmented detector made of thousands of scintillating cubes. SoLid has a very innovative hybrid technology with two different scintillators which have different light emissions: polyvynil-toluene cubes (PVT) to detect the positrons and 6LiF:ZnS sheets on two faces of each PVT cube to detect the neutrons. It allows us to do an efficient pulse shape analysis to identify the signals from neutrons and positrons. The 288 kg detector prototype (SM1) took data in 2015. It demonstrated the detection principle and background rejection efficiency. The construction of SoLid phase I (˜ 1.5 t) has now started. To improve the energy resolution of SoLid phase I, we have tried to increase the light yield studying separately the two scintillators: PVT and ZnS. A test bench has been built to fully characterize and improve the neutron detection with the ZnS using an AmBe source. To study the positron light yield on the PVT, we have built another test bench with a 207Bi source. We have improved the design of the cubes, their wrapping or the type and the configuration of the fibers. We managed to increase the PVT light yield by about 66 % and improve the resolution of the positron energy on the test bench from 21 % to 16 % at 1 MeV.

Analysis of Zinc-Exporters Expression in Prostate Cancer.

PubMed

Singh, Chandra K; Malas, Kareem M; Tydrick, Caitlin; Siddiqui, Imtiaz A; Iczkowski, Kenneth A; Ahmad, Nihal

2016-11-11

Maintaining optimal intracellular zinc (Zn) concentration is crucial for critical cellular functions. Depleted Zn has been associated with prostate cancer (PCa) progression. Solute carrier family 30 (SLC30A) proteins maintain cytoplasmic Zn balance by exporting Zn out to the extracellular space or by sequestering cytoplasmic Zn into intracellular compartments. In this study, we determined the involvement of Zn-exporters, SLC30A 1-10 in PCa, in the context of racial health disparity in human PCa samples obtained from European-American (EA) and African-American (AA) populations. We also analyzed the levels of Zn-exporters in a panel of PCa cells derived from EA and AA populations. We further explored the expression profile of Zn-exporters in PCa using Oncomine database. Zn-exporters were found to be differentially expressed at the mRNA level, with a significant upregulation of SLC30A1, SLC30A9 and SLC30A10, and downregulation of SLC30A5 and SLC30A6 in PCa, compared to benign prostate. Moreover, Ingenuity Pathway analysis revealed several interactions of Zn-exporters with certain tumor suppressor and promoter proteins known to be modulated in PCa. Our study provides an insight regarding Zn-exporters in PCa, which may open new avenues for future studies aimed at enhancing the levels of Zn by modulating Zn-transporters via pharmacological means.

Analysis of Zinc-Exporters Expression in Prostate Cancer

PubMed Central

Singh, Chandra K.; Malas, Kareem M.; Tydrick, Caitlin; Siddiqui, Imtiaz A.; Iczkowski, Kenneth A.; Ahmad, Nihal

2016-01-01

Maintaining optimal intracellular zinc (Zn) concentration is crucial for critical cellular functions. Depleted Zn has been associated with prostate cancer (PCa) progression. Solute carrier family 30 (SLC30A) proteins maintain cytoplasmic Zn balance by exporting Zn out to the extracellular space or by sequestering cytoplasmic Zn into intracellular compartments. In this study, we determined the involvement of Zn-exporters, SLC30A 1–10 in PCa, in the context of racial health disparity in human PCa samples obtained from European-American (EA) and African-American (AA) populations. We also analyzed the levels of Zn-exporters in a panel of PCa cells derived from EA and AA populations. We further explored the expression profile of Zn-exporters in PCa using Oncomine database. Zn-exporters were found to be differentially expressed at the mRNA level, with a significant upregulation of SLC30A1, SLC30A9 and SLC30A10, and downregulation of SLC30A5 and SLC30A6 in PCa, compared to benign prostate. Moreover, Ingenuity Pathway analysis revealed several interactions of Zn-exporters with certain tumor suppressor and promoter proteins known to be modulated in PCa. Our study provides an insight regarding Zn-exporters in PCa, which may open new avenues for future studies aimed at enhancing the levels of Zn by modulating Zn-transporters via pharmacological means. PMID:27833104

Addition of carbonic anhydrase 9 inhibitor SLC-0111 to temozolomide treatment delays glioblastoma growth in vivo

PubMed Central

Boyd, Nathaniel H.; Walker, Kiera; Fried, Joshua; Hackney, James R.; McDonald, Paul C.; Benavides, Gloria A.; Spina, Raffaella; Audia, Alessandra; Scott, Sarah E.; Libby, Catherine J.; Tran, Anh Nhat; Bevensee, Mark O.; Griguer, Corinne; Nozell, Susan; Gillespie, G. Yancey; Nabors, Burt; Bhat, Krishna P.; Bar, Eli E.; Darley-Usmar, Victor; Xu, Bo; Gordon, Emily; Dedhar, Shoukat; Hjelmeland, Anita B.

2017-01-01

Tumor microenvironments can promote stem cell maintenance, tumor growth, and therapeutic resistance, findings linked by the tumor-initiating cell hypothesis. Standard of care for glioblastoma (GBM) includes temozolomide chemotherapy, which is not curative, due, in part, to residual therapy-resistant brain tumor-initiating cells (BTICs). Temozolomide efficacy may be increased by targeting carbonic anhydrase 9 (CA9), a hypoxia-responsive gene important for maintaining the altered pH gradient of tumor cells. Using patient-derived GBM xenograft cells, we explored whether CA9 and CA12 inhibitor SLC-0111 could decrease GBM growth in combination with temozolomide or influence percentages of BTICs after chemotherapy. In multiple GBMs, SLC-0111 used concurrently with temozolomide reduced cell growth and induced cell cycle arrest via DNA damage in vitro. In addition, this treatment shifted tumor metabolism to a suppressed bioenergetic state in vivo. SLC-0111 also inhibited the enrichment of BTICs after temozolomide treatment determined via CD133 expression and neurosphere formation capacity. GBM xenografts treated with SLC-0111 in combination with temozolomide regressed significantly, and this effect was greater than that of temozolomide or SLC-0111 alone. We determined that SLC-0111 improves the efficacy of temozolomide to extend survival of GBM-bearing mice and should be explored as a treatment strategy in combination with current standard of care. PMID:29263302

RNA editing of SLC22A3 drives early tumor invasion and metastasis in familial esophageal cancer

PubMed Central

Fu, Li; Qin, Yan-Ru; Ming, Xiao-Yan; Zuo, Xian-Bo; Diao, Yu-Wen; Zhang, Li-Yi; Ai, Jiaoyu; Liu, Bei-Lei; Huang, Tu-Xiong; Cao, Ting-Ting; Tan, Bin-Bin; Xiang, Di; Zeng, Chui-Mian; Gong, Jing; Zhang, Qiangfeng; Dong, Sui-Sui; Chen, Juan; Liu, Haibo; Wu, Jian-Lin; Qi, Robert Z.; Xie, Dan; Wang, Li-Dong

2017-01-01

Like many complex human diseases, esophageal squamous cell carcinoma (ESCC) is known to cluster in families. Familial ESCC cases often show early onset and worse prognosis than the sporadic cases. However, the molecular genetic basis underlying the development of familial ESCC is mostly unknown. We reported that SLC22A3 is significantly down-regulated in nontumor esophageal tissues from patients with familial ESCC compared with tissues from patients with sporadic ESCCs. A-to-I RNA editing of the SLC22A3 gene results in its reduced expression in the nontumor esophageal tissues of familial ESCCs and is significantly correlated with lymph node metastasis. The RNA-editing enzyme ADAR2, a familial ESCC susceptibility gene identified by our post hoc genome-wide association study, is positively correlated with the editing level of SLC22A3. Moreover, functional studies showed that SLC22A3 is a metastasis suppressor in ESCC, and deregulation of SLC22A3 facilitates cell invasion and filopodia formation by reducing its direct association with α-actinin-4 (ACTN4), leading to the increased actin-binding activity of ACTN4 in normal esophageal cells. Collectively, we now show that A-to-I RNA editing of SLC22A3 contributes to the early development and progression of familial esophageal cancer in high-risk individuals. PMID:28533408

Study and Fabrication of Super Low-Cost Solar Cell (SLC-SC) Based on Counter Electrode from Animal’s Bone

NASA Astrophysics Data System (ADS)

Fadlilah, D. R.; Fajar, M. N.; Aini, A. N.; Haqqiqi, R. I.; Wirawan, P. R.; Endarko

2018-04-01

The synthesized carbon from bones of chicken, cow, and fish with the calcination temperature at 450 and 600°C have been successfully fabricated for counter electrode in the Super Low-Cost Solar Cell (SLC-LC) based the structure of Dye-Sensitized Solar Cells (DSSC). The main proposed study was to fabricate SLC-SC and investigate the influence of the synthesized carbon from animal’s bone for counter electrode towards to photovoltaic performance of SLC-SC. X-Ray Diffraction and UV-Vis was used to characterize the phase and the optical properties of TiO2 as photoanode in SLC-SC. Meanwhile, the morphology and particle size distribution of the synthesized carbon in counter electrodes were investigated by Scanning Electron Microscopy (SEM) and Particle Size Analyzer (PSA). The results showed that the TiO2 has anatase phase with the absorption wavelength of 300 to 550 nm. The calcination temperature for synthesizing of carbon could affect morphology and particle size distribution. The increasing temperature gave the effect more dense in morphology and increased the particle size of carbon in the counter electrode. Changes in morphology and particle size of carbon give effect to the performance of the SLC-SC where the increased morphology’s compact and particle size make decreased in the performance of the SLC-SC.

Impenetrable barriers for positrons in neighbourhood of superheavy nuclei with Z>118

NASA Astrophysics Data System (ADS)

Neznamov, V. P.

2017-12-01

Analysis of quantum mechanical motion of charged half-spin particles in the repulsive Coulomb field results in that an impenetrable potential barrier not explored earlier was found. For a particle at rest with a reduced mass m, the barrier radius is equal to half classical radius: the barrier radius decreases with increase in the particle energy. For the stable and quasi-stable nuclei with Z > 118, presence of an impenetrable barrier as β +-decay leads to the existence of “traps” for positrons in the neighbourhood of nuclei and as Zcr ≃ 170 (with emission of electron-positron pairs by vacuum) leads to the existence of a quasi-constant source of annihilation quanta.

Dense electron-positron plasmas and ultraintense γ rays from laser-irradiated solids.

PubMed

Ridgers, C P; Brady, C S; Duclous, R; Kirk, J G; Bennett, K; Arber, T D; Robinson, A P L; Bell, A R

2012-04-20

In simulations of a 10 PW laser striking a solid, we demonstrate the possibility of producing a pure electron-positron plasma by the same processes as those thought to operate in high-energy astrophysical environments. A maximum positron density of 10(26) m(-3) can be achieved, 7 orders of magnitude greater than achieved in previous experiments. Additionally, 35% of the laser energy is converted to a burst of γ rays of intensity 10(22) W cm(-2), potentially the most intense γ-ray source available in the laboratory. This absorption results in a strong feedback between both pair and γ-ray production and classical plasma physics in the new "QED-plasma" regime.

1. AERIAL VIEW OF SLC3 FROM THE NORTHEAST SHOWING THE ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

1. AERIAL VIEW OF SLC-3 FROM THE NORTHEAST SHOWING THE EAST (LEFT) AND WEST (RIGHT) LAUNCH PADS, AND CABLE TRAYS FROM SLC-3W. SEWAGE TREATMENT PLANT (BLDG. 769) AND STORAGE SHED (BLDG. 773) IN LEFT FOREGROUND. - Vandenberg Air Force Base, Space Launch Complex 3, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

Association analysis of the SLC22A11 (organic anion transporter 4) and SLC22A12 (urate transporter 1) urate transporter locus with gout in New Zealand case-control sample sets reveals multiple ancestral-specific effects

PubMed Central

2013-01-01

Introduction There is inconsistent association between urate transporters SLC22A11 (organic anion transporter 4 (OAT4)) and SLC22A12 (urate transporter 1 (URAT1)) and risk of gout. New Zealand (NZ) Māori and Pacific Island people have higher serum urate and more severe gout than European people. The aim of this study was to test genetic variation across the SLC22A11/SLC22A12 locus for association with risk of gout in NZ sample sets. Methods A total of 12 single nucleotide polymorphism (SNP) variants in four haplotype blocks were genotyped using TaqMan® and Sequenom MassArray in 1003 gout cases and 1156 controls. All cases had gout according to the 1977 American Rheumatism Association criteria. Association analysis of single markers and haplotypes was performed using PLINK and Stata. Results A haplotype block 1 SNP (rs17299124) (upstream of SLC22A11) was associated with gout in less admixed Polynesian sample sets, but not European Caucasian (odds ratio; OR = 3.38, P = 6.1 × 10-4; OR = 0.91, P = 0.40, respectively) sample sets. A protective block 1 haplotype caused the rs17299124 association (OR = 0.28, P = 6.0 × 10-4). Within haplotype block 2 (SLC22A11) we could not replicate previous reports of association of rs2078267 with gout in European Caucasian (OR = 0.98, P = 0.82) sample sets, however this SNP was associated with gout in Polynesian (OR = 1.51, P = 0.022) sample sets. Within haplotype block 3 (including SLC22A12) analysis of haplotypes revealed a haplotype with trans-ancestral protective effects (OR = 0.80, P = 0.004), and a second haplotype conferring protection in less admixed Polynesian sample sets (OR = 0.63, P = 0.028) but risk in European Caucasian samples (OR = 1.33, P = 0.039). Conclusions Our analysis provides evidence for multiple ancestral-specific effects across the SLC22A11/SLC22A12 locus that presumably influence the activity of OAT4 and URAT1 and risk of gout. Further fine mapping of the association signal is needed using trans-ancestral re-sequence data. PMID:24360580

Combination of SLC administration and Tregs depletion is an attractive strategy for targeting hepatocellular carcinoma

PubMed Central

2013-01-01

Background Secondary lymphoid tissue chemokine (SLC) is a key CC chemokine for chemotaxis of immune cells and has been an attractive candidate for anti-tumor treatments. However, among the immune cells recruited by SLC to tumors, the CD25+ Foxp3+ regulatory T cells (Tregs) compromise the anti-tumor effects. In this study, we proposed the combination therapy of intratumoral co-administration of SLC and anti-CD25 monoclonal antibodies (mAbs). We hypothesized that the intratumoral injections of SLC and depletion of Tregs would have stronger inhibition effects on the progression of hepatocellular carcinoma (HCC) in mice. Methods C57BL/6 mice were inoculated subcutaneously with the murine HCC cell line, and mice with visible tumors were treated intratumorally with SLC, SLC plus anti-CD25 mAbs or the control antibodies. The percentages of Tregs, effector CD8+ T cells and CD4+ T cells were checked in the tumors, lymph nodes, spleen and liver at regular intervals. The levels of intratumoral IL-12, IFN-γ, IL-10 and TGF-β1 were evaluated. The final anti-tumor effects were measured by the tumor volume and weight as well as the intratumoral activity of MMP2 and MMP9. Bone-marrow-derived dendritic cells were used to explore the mechanisms of maturation induced by SLC in vitro. Results Our experiments showed the combination therapy significantly decreased the frequency of Tregs, and increased CD8+ T cells and CD4+ T cells at tumor sites. These alterations were accompanied by an increased level of IL-12 and IFN-γ, and decreased level of IL-10 and TGF-β1. Unexpectedly, we observed a significantly decreased percentage of Tregs, and increased CD8+ T cells and CD4+ T cells in the lymph nodes, spleen and liver after the combination therapy. The growth and invasiveness of HCC was also maximally inhibited in the combination therapy compared with the SLC alone. Furthermore, we confirmed SLC induced the maturation of DCs via NF-κB p65 and this maturation would benefit the combination therapy. Conclusions Our data demonstrated that intratumoral co-administration of SLC and anti-CD25 mAbs was an effective treatment for HCC, which was correlated with the altered tumor microenvironment and systemically optimized percentages of Tregs, CD8+ T cells and CD4+ T cells in peripheral immune organs. PMID:24304581

FAST TRACK COMMUNICATION: Stable propagation of a modulated positron beam in a bent crystal channel

NASA Astrophysics Data System (ADS)

Kostyuk, A.; Korol, A. V.; Solov'yov, A. V.; Greiner, W.

2010-08-01

The propagation of a modulated positron beam in a planar crystal channel is investigated. It is demonstrated that the beam preserves its modulation at sufficiently large penetration depths, which opens the prospect of using a crystalline undulator as a coherent source of hard x-rays. This finding is a crucial milestone in developing a new type of laser radiating in the hard x-ray and gamma-ray range.

Yes-associated protein 1 and transcriptional coactivator with PDZ-binding motif activate the mammalian target of rapamycin complex 1 pathway by regulating amino acid transporters in hepatocellular carcinoma.

PubMed

Park, Yun-Yong; Sohn, Bo Hwa; Johnson, Randy L; Kang, Myoung-Hee; Kim, Sang Bae; Shim, Jae-Jun; Mangala, Lingegowda S; Kim, Ji Hoon; Yoo, Jeong Eun; Rodriguez-Aguayo, Cristian; Pradeep, Sunila; Hwang, Jun Eul; Jang, Hee-Jin; Lee, Hyun-Sung; Rupaimoole, Rajesha; Lopez-Berestein, Gabriel; Jeong, Woojin; Park, Inn Sun; Park, Young Nyun; Sood, Anil K; Mills, Gordon B; Lee, Ju-Seog

2016-01-01

Metabolic activation is a common feature of many cancer cells and is frequently associated with the clinical outcomes of various cancers, including hepatocellular carcinoma. Thus, aberrantly activated metabolic pathways in cancer cells are attractive targets for cancer therapy. Yes-associated protein 1 (YAP1) and transcriptional coactivator with PDZ-binding motif (TAZ) are oncogenic downstream effectors of the Hippo tumor suppressor pathway, which is frequently inactivated in many cancers. Our study revealed that YAP1/TAZ regulates amino acid metabolism by up-regulating expression of the amino acid transporters solute carrier family 38 member 1 (SLC38A1) and solute carrier family 7 member 5 (SLC7A5). Subsequently, increased uptake of amino acids by the transporters (SLC38A1 and SLC7A5) activates mammalian target of rapamycin complex 1 (mTORC1), a master regulator of cell growth, and stimulates cell proliferation. We also show that high expression of SLC38A1 and SLC7A5 is significantly associated with shorter survival in hepatocellular carcinoma patients. Furthermore, inhibition of the transporters and mTORC1 significantly blocks YAP1/TAZ-mediated tumorigenesis in the liver. These findings elucidate regulatory networks connecting the Hippo pathway to mTORC1 through amino acid metabolism and the mechanism's potential clinical implications for treating hepatocellular carcinoma. YAP1 and TAZ regulate cancer metabolism and mTORC1 through regulation of amino acid transportation, and two amino acid transporters, SLC38A1 and SLC7A5, might be important therapeutic targets. © 2015 by the American Association for the Study of Liver Diseases.

Genetic polymorphisms in Na+-taurocholate co-transporting polypeptide (NTCP) and ileal apical sodium-dependent bile acid transporter (ASBT) and ethnic comparisons of functional variants of NTCP among Asian populations.

PubMed

Pan, Wei; Song, Im-Sook; Shin, Ho-Jung; Kim, Min-Hye; Choi, Yeong-Lim; Lim, Su-Jeong; Kim, Woo-Young; Lee, Sang-Seop; Shin, Jae-Gook

2011-06-01

Genetic variants of Na(+)-taurocholate co-transporting polypeptide (NTCP; SLC10A1) and ileal apical sodium-dependent bile acid transporter (ASBT; SLC10A2), which greatly contribute to bile acid homeostasis, were extensively explored in the Korean population and functional variants of NTCP were compared among Asian populations. From direct DNA sequencing, six SNPs were identified in the SLC10A1 gene and 14 SNPs in the SLC10A2 gene. Three of seven coding variants were non-synonymous SNPs: two variants from SLC10A1 (A64T, S267F) and one from SLC10A2 (A171S). No linkage was analysed in the SLC10A1 gene because of low frequencies of genetic variants, and the SLC10A2 gene was composed of two separated linkage disequilibrium blocks contrary to the white population. The stably transfected NTCP-A64T variant showed significantly decreased uptakes of taurocholate and rosuvastatin compared with wild-type NTCP. The decreased taurocholate uptake and increased rosuvastatin uptake were shown in the NTCP-S267F variant. The allele frequencies of these functional variants were 1.0% and 3.1%, respectively, in a Korean population. However, NTCP-A64T was not found in Chinese and Vietnamese subjects. The frequency distribution of NTCP-S267F in Koreans was significantly lower than those in Chinese and Vietnamese populations. Our data suggest that NTCP-A64T and -S267F variants cause substrate-dependent functional change in vitro, and show ethnic difference in their allelic frequencies among Asian populations although the clinical relevance of these variants is remained to be evaluated.

DNA methylation of the serotonin transporter gene (SLC6A4) is associated with brain function involved in processing emotional stimuli.

PubMed

Frodl, Thomas; Szyf, Moshe; Carballedo, Angela; Ly, Victoria; Dymov, Sergiy; Vaisheva, Farida; Morris, Derek; Fahey, Ciara; Meaney, James; Gill, Michael; Booij, Linda

2015-09-01

The aim of the present study was to investigate the association of fMRI blood oxygen-level dependent (BOLD) reactivity with the level of epigenetic methylation of SLC6A4 in blood DNA from a sample of healthy participants and patients with major depressive disorder (MDD). We investigated patients with MDD and healthy controls using fMRI and an emotional attention-shifting task. We assessed site-specific DNA methylation of a previously characterized SLC6A4 region in peripheral blood DNA using pyrosequencing. Our study involved 25 patients with MDD and 35 healthy controls. Activation in the anterior insula elicited by negative emotional content was significantly positively associated with the degree of SLC6A4 methylation. Significantly negative associations were observed between activation in the posterior insula and the degree of SLC6A4 methylation when judging the geometry of pictures after seeing negative in contrast to positive emotional stimuli. Healthy controls with a high degree of SLC6A4 methylation depicted significantly more activity elicited by positive stimuli in limbic regions and more activity elicited by negative stimuli in limbic as well as cognitive control regions than those with a low degree of SLC6A4 methylation. It is impossible to measure methylation directly in the brain and thus we assessed peripheral methylation of SLC6A4. Since the association was cross-sectional, no conclusion about cause and effect can be drawn. Our study provides further support to the hypothesis that particular DNA methylation states that are associated with brain function during emotion processing are detectable in the periphery.

Involvement of riboflavin transporter RFVT2/Slc52a2 in hepatic homeostasis of riboflavin in mice.

PubMed

Yao, Yoshiaki; Yonezawa, Atsushi; Yoshimatsu, Hiroki; Omura, Tomohiro; Masuda, Satohiro; Matsubara, Kazuo

2013-08-15

Riboflavin (vitamin B2) acts as an intermediary during various biochemical oxidation-reduction reactions in the liver. Hepatic riboflavin homeostasis is suggested to be maintained through its transporter(s). Riboflavin transporters, RFVT2/Slc52a2 and RFVT3/Slc52a3, have been identified in rodents. However, the role of each RFVT in the hepatic homeostasis of riboflavin has not yet been fully clarified. In this study, we assessed the contribution of each RFVT to riboflavin uptake into the liver using in vitro and in vivo studies. The uptake of riboflavin by mouse primary hepatocytes increased in a time-dependent and a concentration-dependent manner. Riboflavin transport was independent of extracellular Na(+). However, the uptake decreased slightly along with the extracellular pH increases. Real-time PCR analysis revealed that the mRNA level of Slc52a2, or coding for mouse (m)RFVT2, in the mouse liver was 10 times higher than that of Slc52a3 (coding for mRFVT3). The uptake of riboflavin at pH 7.4 by primary hepatocytes was significantly decreased by the transfection of Slc52a2-small interfering RNA (siRNA), but not Slc52a3-siRNA. Furthermore, we also confirmed the contribution of riboflavin transporters in vivo. The riboflavin concentrations in plasma, but not in the liver, were significantly decreased in mice fed on a riboflavin-deficient diet for 8 weeks. The expression of Slc52a2 mRNA was significantly upregulated by riboflavin deprivation. These results strongly suggest that mRFVT2 was involved in hepatic riboflavin homeostasis. © 2013 Elsevier B.V. All rights reserved.

MiR-133 is Involved in Estrogen Deficiency-Induced Osteoporosis through Modulating Osteogenic Differentiation of Mesenchymal Stem Cells.

PubMed

Lv, Hao; Sun, Yujie; Zhang, Yuchen

2015-05-27

MiR-133 expression is dysregulated in postmenopausal osteoporosis. However, its role in postmenopausal osteoporosis is still not well understood. In the current study, we explore how estrogen deficiency affects miR-133 expression and how miR-133 is involved in osteogenic differentiation of mesenchymal stem cells (MSCs). qRT-PCR analysis was performed to assess miR-133 expression in MSCs isolated from bone marrow of an ovariectomized (OVX) animal model and postmenopausal osteoporosis patients (PMOP) and their corresponding controls. The binding between miR-133 and predicted target SLC39A1 was verified using dual luciferase assay and Western blot analysis. The effect of miR-133 and SLC39A1 on osteogenic differentiation of MSCs was assessed through measuring alkaline phosphatase (ALP), mineralization nodules, and osteoblast-specific genes Runx2 and Osterix expression. miR-133 expression is significantly enhanced as a result of estrogen deficiency. Its overexpression is negatively correlated to osteogenic differentiation of hMSCs. SLC39A1 showed an inverse expression trend to miR-133 during the differentiation. miR-133 can directly target 3'UTR of SLC39A1 and thereby modulate its expression in hMSCs. The miR-133-SLC39A1 axis might play an important role in osteogenic differentiation of hMSCs. SLC39A1 can promote ALP activity and formation of mineralization nodules. In addition, SLC39A1 expression level is also positively correlated with RUNX2 and Osterix. Estrogen deficiency is associated with miR-133 overexpression. MiR-133 can induce postmenopausal osteoporosis by weakening osteogenic differentiation of hMSCs, at least partly through repressing SLC39A1 expression.

MiR-133 is Involved in Estrogen Deficiency-Induced Osteoporosis through Modulating Osteogenic Differentiation of Mesenchymal Stem Cells

PubMed Central

Lv, Hao; Sun, Yujie; Zhang, Yuchen

2015-01-01

Background MiR-133 expression is dysregulated in postmenopausal osteoporosis. However, its role in postmenopausal osteoporosis is still not well understood. In the current study, we explore how estrogen deficiency affects miR-133 expression and how miR-133 is involved in osteogenic differentiation of mesenchymal stem cells (MSCs). Material/Methods qRT-PCR analysis was performed to assess miR-133 expression in MSCs isolated from bone marrow of an ovariectomized (OVX) animal model and postmenopausal osteoporosis patients (PMOP) and their corresponding controls. The binding between miR-133 and predicted target SLC39A1 was verified using dual luciferase assay and Western blot analysis. The effect of miR-133 and SLC39A1 on osteogenic differentiation of MSCs was assessed through measuring alkaline phosphatase (ALP), mineralization nodules, and osteoblast-specific genes Runx2 and Osterix expression. Results miR-133 expression is significantly enhanced as a result of estrogen deficiency. Its overexpression is negatively correlated to osteogenic differentiation of hMSCs. SLC39A1 showed an inverse expression trend to miR-133 during the differentiation. miR-133 can directly target 3′UTR of SLC39A1 and thereby modulate its expression in hMSCs. The miR-133-SLC39A1 axis might play an important role in osteogenic differentiation of hMSCs. SLC39A1 can promote ALP activity and formation of mineralization nodules. In addition, SLC39A1 expression level is also positively correlated with RUNX2 and Osterix. Conclusions Estrogen deficiency is associated with miR-133 overexpression. MiR-133 can induce postmenopausal osteoporosis by weakening osteogenic differentiation of hMSCs, at least partly through repressing SLC39A1 expression. PMID:26013661

Ion and solute transport by prestin in Drosophila and Anopheles

PubMed Central

Hirata, Taku; Czapar, Anna; Brin, Lauren R.; Haritonova, Alyona; Bondeson, Daniel P.; Linser, Paul J.; Cabrero, Pablo; Dow, Julian A. T.; Romero, Michael F.

2012-01-01

The gut and Malpighian tubules of insects are the primary sites of active solute and water transport for controlling hemolymph and urine composition, pH, and osmolarity. These processes depend on ATPase (pumps), channels and solute carriers (Slc proteins). Maturation of genomic databases enables us to identify the putative molecular players for these processes. Anion transporters of the Slc4 family, AE1 and NDAE1, have been reported as HCO3− transporters, but are only part of the story. Here we report Dipteran (Drosophila melanogaster (d) and Anopheles gambiae (Ag)) anion exchangers, belonging to the Slc26 family, which are multi-functional anion exchangers. One Drosophila and two Ag homologues of mammalian Slc26a5 (prestin) and Slc26a6 (aka, PAT1, CFEX) were identified and designated dPrestin, AgPrestinA and AgPrestinB. dPrestin and AgPrestinB show electrogenic anion exchange (Cl−/nHCO3−, Cl−/SO42− and Cl−/oxalate2−) in an oocyte expression system. Since these transporters are the only Dipteran Slc26 proteins whose transport is similar to mammalian Slc26a6, we submit that Dipteran Prestin are functional and even molecular orthologues of mammalian Slc26a6. OSR1 kinase increases dPrestin ion transport, implying another set of physiological processes controlled by WNK/SPAK signaling in epithelia. All of these mRNAs are highly expressed in the gut and Malpighian tubules. Dipteran Prestin proteins appear suited for central roles in bicarbonate, sulfate and oxalate metabolism including generating the high pH conditions measured in the Dipteran midgut lumen. Finally, we present and discuss Drosophila genetic models that integrate these processes. PMID:22321763

A Novel SLC27A4 Splice Acceptor Site Mutation in Great Danes with Ichthyosis.

PubMed

Metzger, Julia; Wöhlke, Anne; Mischke, Reinhard; Hoffmann, Annalena; Hewicker-Trautwein, Marion; Küch, Eva-Maria; Naim, Hassan Y; Distl, Ottmar

2015-01-01

Ichthyoses are a group of various different types of hereditary disorders affecting skin cornification. They are characterized by hyperkeratoses of different severity levels and are associated with a dry and scaling skin. Genome-wide association analysis of nine affected and 13 unaffected Great Danes revealed a genome-wide significant peak on chromosome 9 at 57-58 Mb in the region of SLC27A4. Sequence analysis of genomic DNA of SLC27A4 revealed the non-synonymous SNV SLC27A4:g.8684G>A in perfect association with ichthyosis-affection in Great Danes. The mutant transcript of SLC27A4 showed an in-frame loss of 54 base pairs in exon 8 probably induced by a new splice acceptor site motif created by the mutated A- allele of the SNV. Genotyping 413 controls from 35 different breeds of dogs and seven wolves revealed that this mutation could not be found in other populations except in Great Danes. Affected dogs revealed high amounts of mutant transcript but only low levels of the wild type transcript. Targeted analyses of SLC27A4 protein from skin tissues of three affected and two unaffected Great Danes indicated a markedly reduced or not detectable wild type and truncated protein levels in affected dogs but a high expression of wild type SLC27A4 protein in unaffected controls. Our data provide evidence of a new splice acceptor site creating SNV that results in a reduction or loss of intact SLC27A4 protein and probably explains the severe skin phenotype in Great Danes. Genetic testing will allow selective breeding to prevent ichthyosis-affected puppies in the future.

The association between the SLC6A3 VNTR 9-repeat allele and alcoholism-a meta-analysis.

PubMed

Du, Yanlei; Nie, Yuqiang; Li, Yuyuan; Wan, Yu-Jui Y

2011-09-01

Dopamine transporter gene (SLC6A3) represents a promising candidate involved in the development of alcoholism. This study aimed to explore the association between the 9-repeat allele (A9) of a 40-bp variable number tandem repeat (VNTR) polymorphism in the 3' un-translated region (3' UTR) of the SLC6A3 gene and alcoholism. The SLC6A3 VNTR was genotyped by PCR in unrelated Mexican Americans including 337 controls and 365 alcoholics. Pearson's chi-square test or Fisher's exact test was used to compare the genotype and allele distribution. Meta-analyses were performed for population-based case-control association studies of the SLC6A3 VNTR polymorphism with alcoholism. Data were analyzed under random effect models with the Comprehensive Meta-analysis (v.2) statistical software package. In Mexican Americans, no significant difference was found in allele and genotype distribution between controls and alcoholics or between controls and alcoholics with alcohol withdrawal seizure (AWS) or delirium tremens (DT) (unadjusted p > 0.05). A total of 13 research articles were included in the meta-analyses. No significant difference of the SLC6A3 VNTR A9 was noted between controls and alcoholics at the genotypic and allelic level when all ethnic populations, only Caucasian populations, or only Asian populations were considered (p > 0.05). Significant associations were observed between SLC6A3 VNTR A9 and alcoholics with AWS or DT at the genotypic as well as allelic level when all ethnic populations or only Caucasian populations were considered (p < 0.05, OR 1.5-2.1). Meta-analyses suggest a possible association between the SLC6A3 VNTR A9 and alcoholic subgroup with AWS or DT. 2011 by the Research Society on Alcoholism.

Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia.

PubMed

Tuschl, Karin; Meyer, Esther; Valdivia, Leonardo E; Zhao, Ningning; Dadswell, Chris; Abdul-Sada, Alaa; Hung, Christina Y; Simpson, Michael A; Chong, W K; Jacques, Thomas S; Woltjer, Randy L; Eaton, Simon; Gregory, Allison; Sanford, Lynn; Kara, Eleanna; Houlden, Henry; Cuno, Stephan M; Prokisch, Holger; Valletta, Lorella; Tiranti, Valeria; Younis, Rasha; Maher, Eamonn R; Spencer, John; Straatman-Iwanowska, Ania; Gissen, Paul; Selim, Laila A M; Pintos-Morell, Guillem; Coroleu-Lletget, Wifredo; Mohammad, Shekeeb S; Yoganathan, Sangeetha; Dale, Russell C; Thomas, Maya; Rihel, Jason; Bodamer, Olaf A; Enns, Caroline A; Hayflick, Susan J; Clayton, Peter T; Mills, Philippa B; Kurian, Manju A; Wilson, Stephen W

2016-05-27

Although manganese is an essential trace metal, little is known about its transport and homeostatic regulation. Here we have identified a cohort of patients with a novel autosomal recessive manganese transporter defect caused by mutations in SLC39A14. Excessive accumulation of manganese in these patients results in rapidly progressive childhood-onset parkinsonism-dystonia with distinctive brain magnetic resonance imaging appearances and neurodegenerative features on post-mortem examination. We show that mutations in SLC39A14 impair manganese transport in vitro and lead to manganese dyshomeostasis and altered locomotor activity in zebrafish with CRISPR-induced slc39a14 null mutations. Chelation with disodium calcium edetate lowers blood manganese levels in patients and can lead to striking clinical improvement. Our results demonstrate that SLC39A14 functions as a pivotal manganese transporter in vertebrates.

Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism–dystonia

PubMed Central

Tuschl, Karin; Meyer, Esther; Valdivia, Leonardo E.; Zhao, Ningning; Dadswell, Chris; Abdul-Sada, Alaa; Hung, Christina Y.; Simpson, Michael A.; Chong, W. K.; Jacques, Thomas S.; Woltjer, Randy L.; Eaton, Simon; Gregory, Allison; Sanford, Lynn; Kara, Eleanna; Houlden, Henry; Cuno, Stephan M.; Prokisch, Holger; Valletta, Lorella; Tiranti, Valeria; Younis, Rasha; Maher, Eamonn R.; Spencer, John; Straatman-Iwanowska, Ania; Gissen, Paul; Selim, Laila A. M.; Pintos-Morell, Guillem; Coroleu-Lletget, Wifredo; Mohammad, Shekeeb S.; Yoganathan, Sangeetha; Dale, Russell C.; Thomas, Maya; Rihel, Jason; Bodamer, Olaf A.; Enns, Caroline A.; Hayflick, Susan J.; Clayton, Peter T.; Mills, Philippa B.; Kurian, Manju A.; Wilson, Stephen W.

2016-01-01

Although manganese is an essential trace metal, little is known about its transport and homeostatic regulation. Here we have identified a cohort of patients with a novel autosomal recessive manganese transporter defect caused by mutations in SLC39A14. Excessive accumulation of manganese in these patients results in rapidly progressive childhood-onset parkinsonism–dystonia with distinctive brain magnetic resonance imaging appearances and neurodegenerative features on post-mortem examination. We show that mutations in SLC39A14 impair manganese transport in vitro and lead to manganese dyshomeostasis and altered locomotor activity in zebrafish with CRISPR-induced slc39a14 null mutations. Chelation with disodium calcium edetate lowers blood manganese levels in patients and can lead to striking clinical improvement. Our results demonstrate that SLC39A14 functions as a pivotal manganese transporter in vertebrates. PMID:27231142

Efficient injection of an intense positron beam into a dipole magnetic field

NASA Astrophysics Data System (ADS)

Saitoh, H.; Stanja, J.; Stenson, E. V.; Hergenhahn, U.; Niemann, H.; Pedersen, T. Sunn; Stoneking, M. R.; Piochacz, C.; Hugenschmidt, C.

2015-10-01

We have demonstrated efficient injection and trapping of a cold positron beam in a dipole magnetic field configuration. The intense 5 eV positron beam was provided by the NEutron induced POsitron source MUniCh facility at the Heinz Maier-Leibnitz Zentrum, and transported into the confinement region of the dipole field trap generated by a supported, permanent magnet with 0.6 T strength at the pole faces. We achieved transport into the region of field lines that do not intersect the outer wall using the {E}× {B} drift of the positron beam between a pair of tailored plates that created the electric field. We present evidence that up to 38% of the beam particles are able to reach the intended confinement region and make at least a 180° rotation around the magnet where they annihilate on an insertable target. When the target is removed and the {E}× {B} plate voltages are switched off, confinement of a small population persists for on the order of 1 ms. These results lend optimism to our larger aims to apply a magnetic dipole field configuration for trapping of both positrons and electrons in order to test predictions of the unique properties of a pair plasma.

Progress towards an intense beam of positrons created by a Van de Graaff accelerator

NASA Astrophysics Data System (ADS)

Lund, K. R.; Weber, M. H.; Lynn, K. G.; Jennings, J.; Minnal, C.; Narimannezhad, A.; Rao, R.; Monster, K. A. W.

2017-12-01

A 4MV Van de Graaff accelerator was used to induce the nuclear reaction 12C(d,n)13N in order to produce an intense beam of positrons. The graphite target was heated so the radioactive 13N would desorb from the bulk into the vacuum. This radioactive gas is frozen onto a cryogenic freezer where it decays to produce an antiparticle beam of positrons. This high current beam is then guided into a superconducting magnet with field strength up to 7 Tesla where the positrons will be stored in a newly designed Micro-Penning-Malmberg trap. Several source geometries have been experimented on and found a maximum antimatter beam with a positron flux of greater than 0.55 ± 0.03 × 106 e+s-1 was achieved. This beam was produced using a solid rare gas moderator composed of krypton (Kr) at a temperature of 25 ± 5 K. Due to geometric restrictions on this set up and other loss mechanisms, 107-108 e+s-1 of the total number of positrons are lost. Simulations and preliminary experiments suggest a new geometry, currently under testing, will produce a beam of 107 e+s-1 or more. The setup and preliminary results for the new geometry will be discussed as well.

Positron annihilation signatures associated with the outburst of the microquasar V404 Cygni.

PubMed

Siegert, Thomas; Diehl, Roland; Greiner, Jochen; Krause, Martin G H; Beloborodov, Andrei M; Bel, Marion Cadolle; Guglielmetti, Fabrizia; Rodriguez, Jerome; Strong, Andrew W; Zhang, Xiaoling

2016-03-17

Microquasars are stellar-mass black holes accreting matter from a companion star and ejecting plasma jets at almost the speed of light. They are analogues of quasars that contain supermassive black holes of 10(6) to 10(10) solar masses. Accretion in microquasars varies on much shorter timescales than in quasars and occasionally produces exceptionally bright X-ray flares. How the flares are produced is unclear, as is the mechanism for launching the relativistic jets and their composition. An emission line near 511 kiloelectronvolts has long been sought in the emission spectrum of microquasars as evidence for the expected electron-positron plasma. Transient high-energy spectral features have been reported in two objects, but their positron interpretation remains contentious. Here we report observations of γ-ray emission from the microquasar V404 Cygni during a recent period of strong flaring activity. The emission spectrum around 511 kiloelectronvolts shows clear signatures of variable positron annihilation, which implies a high rate of positron production. This supports the earlier conjecture that microquasars may be the main sources of the electron-positron plasma responsible for the bright diffuse emission of annihilation γ-rays in the bulge region of our Galaxy. Additionally, microquasars could be the origin of the observed megaelectronvolt continuum excess in the inner Galaxy.

High resolution Cerenkov light imaging of induced positron distribution in proton therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yamamoto, Seiichi, E-mail: s-yama@met.nagoya-u.ac.jp; Fujii, Kento; Morishita, Yuki

2014-11-01

Purpose: In proton therapy, imaging of the positron distribution produced by fragmentation during or soon after proton irradiation is a useful method to monitor the proton range. Although positron emission tomography (PET) is typically used for this imaging, its spatial resolution is limited. Cerenkov light imaging is a new molecular imaging technology that detects the visible photons that are produced from high-speed electrons using a high sensitivity optical camera. Because its inherent spatial resolution is much higher than PET, the authors can measure more precise information of the proton-induced positron distribution with Cerenkov light imaging technology. For this purpose, theymore » conducted Cerenkov light imaging of induced positron distribution in proton therapy. Methods: First, the authors evaluated the spatial resolution of our Cerenkov light imaging system with a {sup 22}Na point source for the actual imaging setup. Then the transparent acrylic phantoms (100 × 100 × 100 mm{sup 3}) were irradiated with two different proton energies using a spot scanning proton therapy system. Cerenkov light imaging of each phantom was conducted using a high sensitivity electron multiplied charge coupled device (EM-CCD) camera. Results: The Cerenkov light’s spatial resolution for the setup was 0.76 ± 0.6 mm FWHM. They obtained high resolution Cerenkov light images of the positron distributions in the phantoms for two different proton energies and made fused images of the reference images and the Cerenkov light images. The depths of the positron distribution in the phantoms from the Cerenkov light images were almost identical to the simulation results. The decay curves derived from the region-of-interests (ROIs) set on the Cerenkov light images revealed that Cerenkov light images can be used for estimating the half-life of the radionuclide components of positrons. Conclusions: High resolution Cerenkov light imaging of proton-induced positron distribution was possible. The authors conclude that Cerenkov light imaging of proton-induced positron is promising for proton therapy.« less

78. GENERAL VIEW OF SLC3W FUEL APRON FROM NORTH. HELIUM ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

78. GENERAL VIEW OF SLC-3W FUEL APRON FROM NORTH. HELIUM AND NITROGEN STORAGE TANKS AND CONTROL SKIDS IN LEFT CENTER. FUEL STORAGE TANK AND CONTROL SKID IN RIGHT BACKGROUND. SLC-3E MST IN DISTANT RIGHT BACKGROUND. - Vandenberg Air Force Base, Space Launch Complex 3, Launch Pad 3 West, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

SLC44A4 mutation causes autosomal dominant hereditary postlingual non-syndromic mid-frequency hearing loss.

PubMed

Ma, Zhaoxin; Xia, Wenjun; Liu, Fei; Ma, Jing; Sun, Shaoyang; Zhang, Jin; Jiang, Nan; Wang, Xu; Hu, Jiongjiong; Ma, Duan

2017-01-15

Clinical, genetic, and functional investigations were performed to identify the causative mutation in a distinctive Chinese family with postlingual non-syndromic mid-frequency sensorineural hearing loss. Whole-exome sequencing revealed SLC44A4, which encodes the choline transport protein, as the pathogenic gene in this family. In the zebrafish model, downregulation of slc44a4 using morpholinos led to significant abnormalities in the zebrafish inner ear and lateral line neuromasts and contributed, to some extent, to disabilities in hearing and balance. SH-SY5Y cells transfected with SLC44A4 showed higher choline uptake and acetylcholine release than that of cells transfected with mutant SLC44A4. We concluded that mutation of SLC44A4 may cause defects in the Choline- acetylcholine system, which is crucial to the efferent innervation of hair cells in the olivocochlear bundle for the maintenance of physiological function of outer hair cells and the protection of hair cells from acoustic injury, leading to hearing loss. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Slc3a2 Mediates Branched-Chain Amino-Acid-Dependent Maintenance of Regulatory T Cells.

PubMed

Ikeda, Kayo; Kinoshita, Makoto; Kayama, Hisako; Nagamori, Shushi; Kongpracha, Pornparn; Umemoto, Eiji; Okumura, Ryu; Kurakawa, Takashi; Murakami, Mari; Mikami, Norihisa; Shintani, Yasunori; Ueno, Satoko; Andou, Ayatoshi; Ito, Morihiro; Tsumura, Hideki; Yasutomo, Koji; Ozono, Keiichi; Takashima, Seiji; Sakaguchi, Shimon; Kanai, Yoshikatsu; Takeda, Kiyoshi

2017-11-14

Foxp3 + regulatory T (Treg) cells, which suppress immune responses, are highly proliferative in vivo. However, it remains unclear how the active replication of Treg cells is maintained in vivo. Here, we show that branched-chain amino acids (BCAAs), including isoleucine, are required for maintenance of the proliferative state of Treg cells via the amino acid transporter Slc3a2-dependent metabolic reprogramming. Mice fed BCAA-reduced diets showed decreased numbers of Foxp3 + Treg cells with defective in vivo proliferative capacity. Mice lacking Slc3a2 specifically in Foxp3 + Treg cells showed impaired in vivo replication and decreased numbers of Treg cells. Slc3a2-deficient Treg cells showed impaired isoleucine-induced activation of the mTORC1 pathway and an altered metabolic state. Slc3a2 mutant mice did not show an isoleucine-induced increase of Treg cells in vivo and exhibited multi-organ inflammation. Taken together, these findings demonstrate that BCAA controls Treg cell maintenance via Slc3a2-dependent metabolic regulation. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Association of the FGA and SLC6A4 genes with autistic spectrum disorder in a Korean population.

PubMed

Ro, Myungja; Won, Seongsik; Kang, Hyunjun; Kim, Su-Yeon; Lee, Seung Ku; Nam, Min; Bang, Hee Jung; Yang, Jae Won; Choi, Kyung-Sik; Kim, Su Kang; Chung, Joo-Ho; Kwack, Kyubum

2013-01-01

Autism spectrum disorder (ASD) is a neurobiological disorder characterized by distinctive impairments in cognitive function, language, and behavior. Linkage and population studies suggest a genetic association between solute carrier family 6 member 4 (SLC6A4) variants and ASD. Logistic regression was used to identify associations between single-nucleotide polymorphisms (SNPs) and ASD with 3 alternative models (additive, dominant, and recessive). Linear regression analysis was performed to determine the influence of SNPs on Childhood Autism Rating Scale (CARS) scores as a quantitative phenotype. In the present study, we examined the associations of SNPs in the SLC6A4 gene and the fibrinogen alpha chain (FGA) gene. Logistic regression analysis showed a significant association between the risk of ASD and rs2070025 and rs2070011 in the FGA gene. The gene-gene interaction between SLC6A4 and FGA was not significantly associated with ASD susceptibility. However, polymorphisms in both SLC6A4 and the FGA gene significantly affected the symptoms of ASD. Our findings indicate that FGA and SLC6A4 gene interactions may contribute to the phenotypes of ASD rather than the incidence of ASD. © 2013 S. Karger AG, Basel.

SLC30A9 mutation affecting intracellular zinc homeostasis causes a novel cerebro-renal syndrome.

PubMed

Perez, Yonatan; Shorer, Zamir; Liani-Leibson, Keren; Chabosseau, Pauline; Kadir, Rotem; Volodarsky, Michael; Halperin, Daniel; Barber-Zucker, Shiran; Shalev, Hanna; Schreiber, Ruth; Gradstein, Libe; Gurevich, Evgenia; Zarivach, Raz; Rutter, Guy A; Landau, Daniel; Birk, Ohad S

2017-04-01

A novel autosomal recessive cerebro-renal syndrome was identified in consanguineous Bedouin kindred: neurological deterioration was evident as of early age, progressing into severe intellectual disability, profound ataxia, camptocormia and oculomotor apraxia. Brain MRI was normal. Four of the six affected individuals also had early-onset nephropathy with features of tubulo-interstitial nephritis, hypertension and tendency for hyperkalemia, though none had rapid deterioration of renal function. Genome wide linkage analysis identified an ∼18 Mb disease-associated locus on chromosome 4 (maximal logarithm of odds score 4.4 at D4S2971; θ = 0). Whole exome sequencing identified a single mutation in SLC30A9 within this locus, segregating as expected within the kindred and not found in a homozygous state in 300 Bedouin controls. We showed that SLC30A9 (solute carrier family 30 member 9; also known as ZnT-9) is ubiquitously expressed with high levels in cerebellum, skeletal muscle, thymus and kidney. Confocal analysis of SH-SY5Y cells overexpressing SLC30A9 fused to enhanced green fluorescent protein demonstrated vesicular cytosolic localization associated with the endoplasmic reticulum, not co-localizing with endosomal or Golgi markers. SLC30A9 encodes a putative zinc transporter (by similarity) previously associated with Wnt signalling. However, using dual-luciferase reporter assay in SH-SY5Y cells we showed that Wnt signalling was not affected by the mutation. Based on protein modelling, the identified mutation is expected to affect SLC30A9's highly conserved cation efflux domain, putatively disrupting its transmembrane helix structure. Cytosolic Zn2+ measurements in HEK293 cells overexpressing wild-type and mutant SLC30A9 showed lower zinc concentration within mutant rather than wild-type SLC30A9 cells. This suggests that SLC30A9 has zinc transport properties affecting intracellular zinc homeostasis, and that the molecular mechanism of the disease is through defective function of this novel activity of SLC30A9 rather than by a defect in its previously described role in transcriptional activation of Wnt signalling. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

The great galactic centre mystery

NASA Technical Reports Server (NTRS)

Riegler, G. R.

1982-01-01

Gamma-ray observations of the center of the Galaxy show a varying positron-electron annihilation radiation emission, while at radio wavelengths a non-thermal compact source surrounded by ionized gas moving at high velocities can be seen. Line emission maps for atomic and ionized hydrogen and molecular gas suggest gas expulsion and a massive collapsed object. IR observations show that ionized gas in the central few parsecs of the Galactic center is concentrated in at least 14 small clouds. Charge-coupled device images show a pair of faint, very red sources within a few arc seconds of IRS 16 and the compact non-thermal radio source. The positron-electron annihilation line emission implies an annihilation rate of 10 to the 43rd per sec, compared with an observed luminosity at IR wavelengths of 10 to the 40 erg per sec. Some models are briefly discussed.

SLC11A1 polymorphisms and host susceptibility to cutaneous leishmaniasis in Pakistan.

PubMed

Sophie, Mariam; Hameed, Abdul; Muneer, Akhtar; Samdani, Azam J; Saleem, Saima; Azhar, Abid

2017-01-07

The vector-borne cutaneous leishmaniasis (CL) is endemic in several regions of Pakistan mainly affecting poor populations. Host genetic factors, particularly SLC11A1 (solute carrier transmembrane protein) within macrophages, play a crucial role in disease pathology and susceptibility. Association of SLC11A1 with cutaneous leishmaniasis, a neglected tropical disease, is not well established. Inconsistencies have been observed within different populations worldwide with respect to genetic susceptibility. This study was designed to investigate genetic variation(s) in SLC11A1 and to assess possible association with cutaneous leishmaniasis in Pakistan. Eight polymorphisms (rs2276631, rs3731864, rs2290708, rs2695342, rs201565523, rs17215556, rs17235409, rs17235416) were genotyped across SLC11A1 in 274 patients and 119 healthy controls. Six polymorphisms were studied by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequencing. Two single nucleotide polymorphisms were analyzed with newly designed semi-nested PCR assays. Case-control analysis showed no association between selected polymorphisms in SLC11A1 and cutaneous leishmaniasis. No significant difference was observed in the distribution of alleles between leishmaniasis patients and healthy individuals. Strong pairwise linkage disequilibrium was observed between rs2276631 and rs2290708 (r 2  = 64); and rs17235409 and rs17235416 (r 2  = 78). This study shows that genetic variations in the candidate gene SLC11A1 do not affect susceptibility to cutaneous leishmaniasis in the sample population from Pakistan.

Evaluation of non-coding variation in GLUT1 deficiency.

PubMed

Liu, Yu-Chi; Lee, Jia Wei Audrey; Bellows, Susannah T; Damiano, John A; Mullen, Saul A; Berkovic, Samuel F; Bahlo, Melanie; Scheffer, Ingrid E; Hildebrand, Michael S

2016-12-01

Loss-of-function mutations in SLC2A1, encoding glucose transporter-1 (GLUT-1), lead to dysfunction of glucose transport across the blood-brain barrier. Ten percent of cases with hypoglycorrhachia (fasting cerebrospinal fluid [CSF] glucose <2.2mmol/L) do not have mutations. We hypothesized that GLUT1 deficiency could be due to non-coding SLC2A1 variants. We performed whole exome sequencing of one proband with a GLUT1 phenotype and hypoglycorrhachia negative for SLC2A1 sequencing and copy number variants. We studied a further 55 patients with different epilepsies and low CSF glucose who did not have exonic mutations or copy number variants. We sequenced non-coding promoter and intronic regions. We performed mRNA studies for the recurrent intronic variant. The proband had a de novo splice site mutation five base pairs from the intron-exon boundary. Three of 55 patients had deep intronic SLC2A1 variants, including a recurrent variant in two. The recurrent variant produced less SLC2A1 mRNA transcript. Fasting CSF glucose levels show an age-dependent correlation, which makes the definition of hypoglycorrhachia challenging. Low CSF glucose levels may be associated with pathogenic SLC2A1 mutations including deep intronic SLC2A1 variants. Extending genetic screening to non-coding regions will enable diagnosis of more patients with GLUT1 deficiency, allowing implementation of the ketogenic diet to improve outcomes. © 2016 Mac Keith Press.

Illustrating the (in)visible: Understanding the impact of loss in adults living with secondary lymphedema after cancer

PubMed Central

Thomas, Roanne; Hamilton, Ryan

2014-01-01

Life with a disability is often riddled with paradoxes, one of which is being visibly marked, while personal experiences, losses, and challenges remain hidden. Our article draws attention to this paradox among people who live with secondary lymphedema after cancer (SLC). SLC is a relatively unfamiliar chronic condition within medical and lay discourses of cancer, which proves challenging for the many cancer survivors who are in search of information and understanding. Thirteen men and women with SLC were recruited from two research sites (Fredericton, NB, and Ottawa, ON, Canada) to participate in semi-structured interviews about the physical and psychosocial aspects of SLC. Using a methodology of interpretive description, our analysis of participant interviews reveals the complex ways in which men and women felt both visible and invisible within various contexts. We discuss three majors themes: (in)visibility and appearance related to material losses; (in)visibility and action connected to visible losses in function, as well as invisible struggles to care for oneself; and the loss of present and future well-being, as SLC renders some limitations visible while potentially obscuring a hopeful future indefinitely. Our research indicates that timely diagnosis of SLC would be an immediate first step in recognizing the physical and emotional dimensions of the condition. To accomplish this, increased awareness is needed. To enhance quality of life for those living with SLC, the development of new resources and psychosocial supports is also required. PMID:25148936

Application of Adaptive Starling-Like Controller to Total Artificial Heart Using Dual Rotary Blood Pumps.

PubMed

Ng, Boon C; Smith, Peter A; Nestler, Frank; Timms, Daniel; Cohn, William E; Lim, Einly

2017-03-01

The successful clinical applicability of rotary left ventricular assist devices (LVADs) has led to research interest in devising a total artificial heart (TAH) using two rotary blood pumps (RBPs). The major challenge when using two separately controlled LVADs for TAH support is the difficulty in maintaining the balance between pulmonary and systemic blood flows. In this study, a starling-like controller (SLC) hybridized with an adaptive mechanism was developed for a dual rotary LVAD TAH. The incorporation of the adaptive mechanism was intended not only to minimize the risk of pulmonary congestion and atrial suction but also to match cardiac demand. A comparative assessment was performed between the proposed adaptive starling-like controller (A-SLC) and a conventional SLC as well as a constant speed controller. The performance of all controllers was evaluated by subjecting them to three simulated scenarios [rest, exercise, head up tilt (HUT)] using a mock circulation loop. The overall results showed that A-SLC was superior in matching pump flow to cardiac demand without causing hemodynamic instabilities. In contrast, improper flow regulation by the SLC resulted in pulmonary congestion during exercise. From resting supine to HUT, overpumping of the RBPs at fixed speed (FS) caused atrial suction, whereas implementation of SLC resulted in insufficient flow. The comparative study signified the potential of the proposed A-SLC for future TAH implementation particularly among outpatients, who are susceptible to variety of clinical scenarios.

Association between norepinephrine transporter gene (SLC6A2) polymorphisms and suicide in patients with major depressive disorder.

PubMed

Kim, Yong-Ku; Hwang, Jung-A; Lee, Heon-Jeong; Yoon, Ho-Kyoung; Ko, Young-Hoon; Lee, Bun-Hee; Jung, Han-Yong; Hahn, Sang-Woo; Na, Kyoung-Sae

2014-04-01

Although several studies have investigated possible associations between norepinephrine neurotransmitter transporter gene (SLC6A2) polymorphisms and depression, few studies have examined associations between SLC6A2 polymorphisms and suicide. Three single-nucleotide polymorphisms (rs2242446, rs28386840, and rs5569) were measured in 550 patients: 201 with major depressive disorder (MDD) and suicide attempt/s, 160 with MDD without suicide attempts, and 189 healthy controls. Analysis of single-nucleotide polymorphisms (SNPs) and haplotype was conducted for the three groups. Subsequently, multivariate logistic regression analysis adjusting for age and gender was conducted to identify independent influences of each SNP. A possible association between suicide lethality and SLC6A2 polymorphisms was also investigated. In the genotype and allele frequency analysis, there were significant differences in rs28386840 between suicidal MDD patients and healthy controls. In the haplotype analysis, TAA (rs2242446-rs28386840-rs5569, from left to right) was associated with suicide attempts in MDD, although the significance (p=0.043) disappeared after Bonferroni correction. There were no relationships between lethality scores and SLC6A2 polymorphisms in suicidal MDD. Modest sample size and a single type of neurotransmitter analyzed (norepinephrine) are the primary limitations. Our results suggest that SLC6A2 polymorphisms were associated with suicide risk in patients with MDD. Future studies are warranted to elucidate possible mechanisms by which SLC6A2 polymorphisms influence suicide risk. Copyright © 2014 Elsevier B.V. All rights reserved.

Total Zinc Intake May Modify the Glucose-Raising Effect of a Zinc Transporter (SLC30A8) Variant

PubMed Central

Kanoni, Stavroula; Nettleton, Jennifer A.; Hivert, Marie-France; Ye, Zheng; van Rooij, Frank J.A.; Shungin, Dmitry; Sonestedt, Emily; Ngwa, Julius S.; Wojczynski, Mary K.; Lemaitre, Rozenn N.; Gustafsson, Stefan; Anderson, Jennifer S.; Tanaka, Toshiko; Hindy, George; Saylor, Georgia; Renstrom, Frida; Bennett, Amanda J.; van Duijn, Cornelia M.; Florez, Jose C.; Fox, Caroline S.; Hofman, Albert; Hoogeveen, Ron C.; Houston, Denise K.; Hu, Frank B.; Jacques, Paul F.; Johansson, Ingegerd; Lind, Lars; Liu, Yongmei; McKeown, Nicola; Ordovas, Jose; Pankow, James S.; Sijbrands, Eric J.G.; Syvänen, Ann-Christine; Uitterlinden, André G.; Yannakoulia, Mary; Zillikens, M. Carola; Wareham, Nick J.; Prokopenko, Inga; Bandinelli, Stefania; Forouhi, Nita G.; Cupples, L. Adrienne; Loos, Ruth J.; Hallmans, Goran; Dupuis, Josée; Langenberg, Claudia; Ferrucci, Luigi; Kritchevsky, Stephen B.; McCarthy, Mark I.; Ingelsson, Erik; Borecki, Ingrid B.; Witteman, Jacqueline C.M.; Orho-Melander, Marju; Siscovick, David S.; Meigs, James B.; Franks, Paul W.; Dedoussis, George V.

2011-01-01

OBJECTIVE Many genetic variants have been associated with glucose homeostasis and type 2 diabetes in genome-wide association studies. Zinc is an essential micronutrient that is important for β-cell function and glucose homeostasis. We tested the hypothesis that zinc intake could influence the glucose-raising effect of specific variants. RESEARCH DESIGN AND METHODS We conducted a 14-cohort meta-analysis to assess the interaction of 20 genetic variants known to be related to glycemic traits and zinc metabolism with dietary zinc intake (food sources) and a 5-cohort meta-analysis to assess the interaction with total zinc intake (food sources and supplements) on fasting glucose levels among individuals of European ancestry without diabetes. RESULTS We observed a significant association of total zinc intake with lower fasting glucose levels (β-coefficient ± SE per 1 mg/day of zinc intake: −0.0012 ± 0.0003 mmol/L, summary P value = 0.0003), while the association of dietary zinc intake was not significant. We identified a nominally significant interaction between total zinc intake and the SLC30A8 rs11558471 variant on fasting glucose levels (β-coefficient ± SE per A allele for 1 mg/day of greater total zinc intake: −0.0017 ± 0.0006 mmol/L, summary interaction P value = 0.005); this result suggests a stronger inverse association between total zinc intake and fasting glucose in individuals carrying the glucose-raising A allele compared with individuals who do not carry it. None of the other interaction tests were statistically significant. CONCLUSIONS Our results suggest that higher total zinc intake may attenuate the glucose-raising effect of the rs11558471 SLC30A8 (zinc transporter) variant. Our findings also support evidence for the association of higher total zinc intake with lower fasting glucose levels. PMID:21810599

105. VIEW NORTH FROM SLC3W CABLE TUNNEL INTO CABLE VAULT ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

105. VIEW NORTH FROM SLC-3W CABLE TUNNEL INTO CABLE VAULT AND SLC-3E CABLE TUNNEL. NOTE WOODEN PLANKING ON FLOOR OF TUNNEL AND CABLE TRAYS LINING TUNNEL WALLS. STAIRS ON EAST WALL OF CABLE VAULT LEAD INTO LANDLINE INSTRUMENTATION ROOM. - Vandenberg Air Force Base, Space Launch Complex 3, Launch Operations Building, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

Complex Analysis of Urate Transporters SLC2A9, SLC22A12 and Functional Characterization of Non-Synonymous Allelic Variants of GLUT9 in the Czech Population: No Evidence of Effect on Hyperuricemia and Gout

PubMed Central

Hurba, Olha; Mancikova, Andrea; Krylov, Vladimir; Pavlikova, Marketa; Pavelka, Karel; Stibůrková, Blanka

2014-01-01

Objective Using European descent Czech populations, we performed a study of SLC2A9 and SLC22A12 genes previously identified as being associated with serum uric acid concentrations and gout. This is the first study of the impact of non-synonymous allelic variants on the function of GLUT9 except for patients suffering from renal hypouricemia type 2. Methods The cohort consisted of 250 individuals (150 controls, 54 nonspecific hyperuricemics and 46 primary gout and/or hyperuricemia subjects). We analyzed 13 exons of SLC2A9 (GLUT9 variant 1 and GLUT9 variant 2) and 10 exons of SLC22A12 by PCR amplification and sequenced directly. Allelic variants were prepared and their urate uptake and subcellular localization were studied by Xenopus oocytes expression system. The functional studies were analyzed using the non-parametric Wilcoxon and Kruskall-Wallis tests; the association study used the Fisher exact test and linear regression approach. Results We identified a total of 52 sequence variants (12 unpublished). Eight non-synonymous allelic variants were found only in SLC2A9: rs6820230, rs2276961, rs144196049, rs112404957, rs73225891, rs16890979, rs3733591 and rs2280205. None of these variants showed any significant difference in the expression of GLUT9 and in urate transport. In the association study, eight variants showed a possible association with hyperuricemia. However, seven of these were in introns and the one exon located variant, rs7932775, did not show a statistically significant association with serum uric acid concentration. Conclusion Our results did not confirm any effect of SLC22A12 and SLC2A9 variants on serum uric acid concentration. Our complex approach using association analysis together with functional and immunohistochemical characterization of non-synonymous allelic variants did not show any influence on expression, subcellular localization and urate uptake of GLUT9. PMID:25268603

Study of the surface contamination of copper with the improved positron annihilation-induced Auger electron spectrometer at NEPOMUC

NASA Astrophysics Data System (ADS)

Mayer, J.; Hugenschmidt, C.; Schreckenbach, K.

2008-10-01

The high intensity positron source NEPOMUC at the FRM-II in Munich enables measurement times for positron annihilation-induced Auger electron spectroscopy (PAES) of only 2.4 h/spectrum, in contrast to usual lab beams with measurement times up to several days. The high electron background due to surrounding experiments in the experimental hall of the FRM-II has been eliminated and hence background free experiments have become possible. Due to this, the signal to noise ratio has been enhanced to 4.5:1, compared to 1:3 with EAES. In addition, a long-term measurement has been performed in order to observe the contamination of a polycrystalline copper foil at 150 °C.

Synchrotron VUV-UV and positron lifetime spectroscopy study of vacancy-type defects in reactor neutron-irradiated MgO.nAl2O3 (n = 2)

NASA Astrophysics Data System (ADS)

Rahman, Abu Zayed Mohammad Saliqur; Cao, Xingzhong; Wang, Baoyi; Evslin, Jarah; Xu, Qiu; Atobe, Kozo

2016-12-01

We investigated neutron-irradiation-induced point defects in spinel single crystals using a synchrotron VUV-UV source and positron lifetime spectroscopy. Photoexcitation (PE) spectra near 230 nm and their corresponding photoluminescence (PL) spectra at 475 nm were attributed to F-centers. With increasing irradiation temperature and fluence, PE efficiency and PL intensity decreased dramatically. Positron lifetimes (PLT) of neutron-irradiated and non-irradiated samples were measured to identify the cation vacancies. A PLT measurement of 250 ps was obtained in a neutron-irradiated (20 K) sample which is tentatively attributed to an aluminum monovacancy. Decreasing PLT with higher irradiation indicates the formation of oxygen-vacancy complex centers.

Investigation of soft component in cosmic ray detection

NASA Astrophysics Data System (ADS)

Oláh, László; Varga, Dezső

2017-07-01

Cosmic ray detection is a research area which finds various applications in tomographic imaging of large size objects. In such applications, the background sources which contaminate cosmic muon signal require a good understanding of the creation processes, as well as reliable simulation frameworks with high predictive power are needed. One of the main background source is the ;soft component;, that is electrons and positrons. In this paper a simulation framework based on GEANT4 has been established to pin down the key features of the soft component. We have found that the electron and positron flux shows a remarkable invariance against various model parameters including the muon emission altitude or primary particle energy distribution. The correlation between simultaneously arriving particles have been quantitatively investigated, demonstrating that electrons and positrons tend to arrive within a close distance and with low relative angle. This feature, which is highly relevant for counting detectors, has been experimentally verified under open sky and at shallow depth underground. The simulation results have been compared to existing other measurements as well as other simulation programs.

Oestrogen upregulates the expression levels and functional activities of duodenal mucosal CFTR and SLC26A6.

PubMed

Jin, Hai; Wen, Guorong; Deng, Shili; Wan, Shuo; Xu, Jingyu; Liu, Xuemei; Xie, Rui; Dong, Hui; Tuo, Biguang

2016-11-01

What is the central question of this study? Duodenal ulcer is a common disease. A sex-based difference in the incidence of duodenal ulcer has long been observed clinically, but the cause is unclear. What is the main finding and its importance? Duodenal mucosal bicarbonate secretion is the most important protective factor in duodenal mucosa against acid-induced damage. The cystic fibrosis transmembrane conductance regulator (CFTR) and the solute-linked carrier 26 gene family A6 (SLC26A6) are two key bicarbonate transport proteins that mediate duodenal mucosal bicarbonate secretion. We demonstrate that endogenous oestrogen upregulates the expression levels and functional activities of duodenal mucosal CFTR and SLC26A6, which contributes to the sex difference in the prevalence of duodenal ulcer. The incidence of duodenal ulcer is markedly lower in women than men, but the cause of the sex difference is not clear. The cystic fibrosis transmembrane conductance regulator (CFTR) and the solute-linked carrier 26 gene family A6 (SLC26A6) are two key bicarbonate transport proteins that mediate duodenal mucosal bicarbonate secretion, which is an important protective factor against acid-induced duodenal injury. The aim of this study was to investigate the effect of oestrogen on the expressions and functional activities of CFTR and SLC26A6 in duodenal mucosa. We found that the expression levels of duodenal CFTR and SLC26A6 were markedly higher in young (20- to 30-year-old) women than in young men and old (60- to 70-year-old) women and men. The expression levels of CFTR and SLC26A6 in young women were markedly higher in preovulatory phases than in premenstrual phases, which was consistent with the changes of serum estradiol concentrations. Further results showed that duodenal CFTR and SLC26A6 expression levels in female mice were markedly decreased after ovariectomy, and supplementation with estradiol reversed the changes in CFTR and SLC26A6. 17β-Estradiol increased CFTR and SLC26A6 expression levels of human duodenocytes in experiments in vitro. Functional experiments showed that basal and forskolin- and prostaglandin E 2 -stimulated duodenal bicarbonate secretion in ovariectomized mice was markedly decreased and, likewise, supplementation with 17β-estradiol reversed the changes. In conclusion, endogenous oestrogen upregulates the expressions and functional activities of CFTR and SLC26A6 in duodenal mucosa, which could contribute to protection of the duodenum and explain the sex difference in the prevalence of duodenal ulcer. © 2016 The Authors. Experimental Physiology © 2016 The Physiological Society.

Screening for X-linked creatine transporter (SLC6A8) deficiency via simultaneous determination of urinary creatine to creatinine ratio by tandem mass-spectrometry.

PubMed

Mercimek-Mahmutoglu, Saadet; Muehl, Adolf; Salomons, Gajja S; Neophytou, Birgit; Moeslinger, Dorothea; Struys, Eduard; Bodamer, Olaf A; Jakobs, Cornelis; Stockler-Ipsiroglu, Sylvia

2009-04-01

High urinary creatine to creatinine ratio (U-CrCrtR) is a potential diagnostic marker of X-linked creatine transporter (SLC6A8) deficiency. We developed a tandem mass-spectrometry method to simultaneously determine urinary creatine and creatinine in 975 individuals (0-18 years). U-CrCrtR increased up to 8 years and decreased thereafter. U-CrCrtR was 2.29 and 2.12 (99th percentile: 1.87) in two males with subsequently confirmed SLC6A8 mutations. The frequency of SLC6A8 deficiency was 2.3% in 157 males at risk.

Evaluation of ion-implanted-silicon detectors for use in intraoperative positron-sensitive probes.

PubMed

Raylman, R R; Wahl, R L

1996-11-01

The continuing development of probes for use with beta (positron and electron) emitting radionuclides may result in more complete excision of tracer-avid tumors. Perhaps one of the most promising radiopharmaceuticals for this task is 18F-labeled-Fluoro-2-Deoxy-D-Glucose (FDG). This positron-emitting agent has been demonstrated to be avidly and rapidly absorbed by many human cancers. We have investigated the use of ion-implanted-silicon detectors in intraoperative positron-sensitive surgical probes for use with FDG. These detectors possess very high positron detection efficiency, while the efficiency for 511 keV photon detection is low. The spatial resolution, as well as positron and annihilation photon detection sensitivity, of an ion-implanted-silicon detector used with 18F was measured at several energy thresholds. In addition, the ability of the device to detect the presence of relatively small amounts of FDG during surgery was evaluated by simulating a surgical field in which some tumor was left intact following lesion excision. The performance of the ion-implanted-silicon detector was compared to the operating characteristics of a positron-sensitive surgical probe which utilizes plastic scintillator. In all areas of performance the ion-implanted-silicon detector proved superior to the plastic scintillator-based probe. At an energy threshold of 14 keV positron sensitivity measured for the ion-implanted-silicon detector was 101.3 cps/kBq, photon sensitivity was 7.4 cps/kBq. In addition, spatial resolution was found to be relatively unaffected by the presence of distant sources of annihilation photon flux. Finally, the detector was demonstrated to be able to localize small amounts of FDG in a simulated tumor bed; indicating that this device has promise as a probe to aid in FDG-guided surgery.

BCA-1 is highly expressed in Helicobacter pylori–induced mucosa-associated lymphoid tissue and gastric lymphoma

PubMed Central

Mazzucchelli, Luca; Blaser, Andrea; Kappeler, Andreas; Schärli, Patrik; Laissue, Jean A.; Baggiolini, Marco; Uguccioni, Mariagrazia

1999-01-01

Infection with Helicobacter pylori (Hp) induces the formation of lymphoid tissue in the stomach and the occasional development of primary gastric B-cell lymphomas. We have studied the expression of 2 chemokines that attract B lymphocytes, BCA-1 and SLC, in gastric tissue samples obtained from patients with chronic gastritis induced by Hp infection or nonsteroidal anti-inflammatory drugs, as well as from patients with Hp-associated low-grade and high-grade gastric lymphomas. High-level expression of BCA-1 and its receptor, CXCR5, was observed in all mucosal lymphoid aggregates and in the mantle zone of all secondary lymphoid follicles in Hp-induced gastric mucosa-associated lymphoid tissue (MALT). Follicular dendritic cells and B lymphocytes are possible sources of BCA-1, which is not expressed by T lymphocytes, macrophages, or CD1a+ dendritic cells. Strong expression of BCA-1 and CXCR5 was also detected in the transformed B cells of gastric MALT lymphomas. By contrast, SLC was confined almost exclusively to endothelial cells in and outside the lymphoid tissue. Only scant, occasional SLC expression was observed in the marginal zone of MALT follicles. Our findings indicate that BCA-1, which functions as a homing chemokine in normal lymphoid tissue, is induced in chronic Hp gastritis and is involved in the formation of lymphoid follicles and gastric lymphomas of the MALT type. J. Clin. Invest. 104:R49–R54 (1999). PMID:10562310

The cyanobacterial bicarbonate transporter BicA: its physiological role and the implications of structural similarities with human SLC26 transporters.

PubMed

Price, G Dean; Howitt, Susan M

2011-04-01

The cyanobacterial Na+-dependent HCO3- transporter BicA is a member of the ubiquitous and important SulP/SLC26 family of anion transporters found in eukaryotes and prokaryotes. BicA is an important component of the cyanobacterial CO2 concentrating mechanism, an adaptation that contributes to cyanobacteria being able to achieve an estimated 25% of global primary productivity, largely in the oceans. The human SLC26 members are involved in a range of key cellular functions involving a diverse range of anion transport activities including Cl-/HCO3-, I-/HCO3-, and SO42-/HCO3- exchange; mutations in SLC26 members are known to be associated with debilitating diseases such as Pendred syndrome, chondrodysplasias, and congenital chloride diarrhoea. We have recently experimentally determined the membrane topology of BicA using the phoA-lacZ reporter system and here consider some of the extrapolated implications for topology of the human SLC26 family and the Sultr plant sulphate transporters.

Influence of SLC6A3 and COMT Variation on Neural Activation During Response Inhibition

PubMed Central

Congdon, Eliza; Constable, R. Todd; Lesch, Klaus Peter; Canli, Turhan

2009-01-01

There is evidence concerning the neural and genetic correlates of inhibitory control, but there have been limited attempts to combine this information. This study tested the hypothesis that two dopaminergic polymorphisms, SLC6A3 and COMT, influence neural activation during response inhibition. Healthy adults were genotyped for these polymorphisms and performed a measure of response inhibition while undergoing functional magnetic resonance imaging (fMRI). Results support the role of key frontostriatal regions underlying response inhibition. Furthermore, results support a significant influence of SLC6A3 and COMT variants on neural activity during inhibition, with greater activation during inhibition in carriers of the SLC6A3 9-allele or the COMT met-allele as compared to carriers of the SLC6A3 10/10 genotype or the COMT val/val genotype. These results add to a growing literature suggesting that inhibitory control is sensitive to variation in dopamine function, and suggest that this variation may be detectable at the level of individuals’ genotypes. PMID:19482231

Bicarbonate transporters in corals point towards a key step in the evolution of cnidarian calcification.

PubMed

Zoccola, Didier; Ganot, Philippe; Bertucci, Anthony; Caminiti-Segonds, Natacha; Techer, Nathalie; Voolstra, Christian R; Aranda, Manuel; Tambutté, Eric; Allemand, Denis; Casey, Joseph R; Tambutté, Sylvie

2015-06-04

The bicarbonate ion (HCO3(-)) is involved in two major physiological processes in corals, biomineralization and photosynthesis, yet no molecular data on bicarbonate transporters are available. Here, we characterized plasma membrane-type HCO3(-) transporters in the scleractinian coral Stylophora pistillata. Eight solute carrier (SLC) genes were found in the genome: five homologs of mammalian-type SLC4 family members, and three of mammalian-type SLC26 family members. Using relative expression analysis and immunostaining, we analyzed the cellular distribution of these transporters and conducted phylogenetic analyses to determine the extent of conservation among cnidarian model organisms. Our data suggest that the SLC4γ isoform is specific to scleractinian corals and responsible for supplying HCO3(-) to the site of calcification. Taken together, SLC4γ appears to be one of the key genes for skeleton building in corals, which bears profound implications for our understanding of coral biomineralization and the evolution of scleractinian corals within cnidarians.

Nutrient transport in the mammary gland: calcium, trace minerals and water soluble vitamins.

PubMed

Montalbetti, Nicolas; Dalghi, Marianela G; Albrecht, Christiane; Hediger, Matthias A

2014-03-01

Milk nutrients are secreted by epithelial cells in the alveoli of the mammary gland by several complex and highly coordinated systems. Many of these nutrients are transported from the blood to the milk via transcellular pathways that involve the concerted activity of transport proteins on the apical and basolateral membranes of mammary epithelial cells. In this review, we focus on transport mechanisms that contribute to the secretion of calcium, trace minerals and water soluble vitamins into milk with particular focus on the role of transporters of the SLC series as well as calcium transport proteins (ion channels and pumps). Numerous members of the SLC family are involved in the regulation of essential nutrients in the milk, such as the divalent metal transporter-1 (SLC11A2), ferroportin-1 (SLC40A1) and the copper transporter CTR1 (SLC31A1). A deeper understanding of the physiology and pathophysiology of these transporters will be of great value for drug discovery and treatment of breast diseases.

Electric-field distribution in Au-semi-insulating GaAs contact investigated by positron-lifetime technique

NASA Astrophysics Data System (ADS)

Ling, C. C.; Shek, Y. F.; Huang, A. P.; Fung, S.; Beling, C. D.

1999-02-01

Positron-lifetime spectroscopy has been used to investigate the electric-field distribution occurring at the Au-semi-insulating GaAs interface. Positrons implanted from a 22Na source and drifted back to the interface are detected through their characteristic lifetime at interface traps. The relative intensity of this fraction of interface-trapped positrons reveals that the field strength in the depletion region saturates at applied biases above 50 V, an observation that cannot be reconciled with a simple depletion approximation model. The data, are, however, shown to be fully consistent with recent direct electric-field measurements and the theoretical model proposed by McGregor et al. [J. Appl. Phys. 75, 7910 (1994)] of an enhanced EL2+ electron-capture cross section above a critical electric field that causes a dramatic reduction of the depletion region's net charge density. Two theoretically derived electric field profiles, together with an experimentally based profile, are used to estimate a positron mobility of ~95+/-35 cm2 V-1 s-1 under the saturation field. This value is higher than previous experiments would suggest, and reasons for this effect are discussed.

The renal urate transporter SLC17A1 locus: confirmation of association with gout.

PubMed

Hollis-Moffatt, Jade E; Phipps-Green, Amanda J; Chapman, Brett; Jones, Gregory T; van Rij, Andre; Gow, Peter J; Harrison, Andrew A; Highton, John; Jones, Peter B; Montgomery, Grant W; Stamp, Lisa K; Dalbeth, Nicola; Merriman, Tony R

2012-04-27

Two major gout-causing genes have been identified, the urate transport genes SLC2A9 and ABCG2. Variation within the SLC17A1 locus, which encodes sodium-dependent phosphate transporter 1, a renal transporter of uric acid, has also been associated with serum urate concentration. However, evidence for association with gout is equivocal. We investigated the association of the SLC17A1 locus with gout in New Zealand sample sets. Five variants (rs1165196, rs1183201, rs9358890, rs3799344, rs12664474) were genotyped across a New Zealand sample set totaling 971 cases and 1,742 controls. Cases were ascertained according to American Rheumatism Association criteria. Two population groups were studied: Caucasian and Polynesian. At rs1183201 (SLC17A1), evidence for association with gout was observed in both the Caucasian (odds ratio (OR) = 0.67, P = 3.0 × 10-6) and Polynesian (OR = 0.74, P = 3.0 × 10-3) groups. Meta-analysis confirmed association of rs1183201 with gout at a genome-wide level of significance (OR = 0.70, P = 3.0 × 10-8). Haplotype analysis suggested the presence of a common protective haplotype. We confirm the SLC17A1 locus as the third associated with gout at a genome-wide level of significance.

A multi-scale segmentation approach to filling gaps in Landsat ETM+ SLC-off images

USGS Publications Warehouse

Maxwell, S.K.; Schmidt, Gail L.; Storey, James C.

2007-01-01

On 31 May 2003, the Landsat Enhanced Thematic Plus (ETM+) Scan Line Corrector (SLC) failed, causing the scanning pattern to exhibit wedge-shaped scan-to-scan gaps. We developed a method that uses coincident spectral data to fill the image gaps. This method uses a multi-scale segment model, derived from a previous Landsat SLC-on image (image acquired prior to the SLC failure), to guide the spectral interpolation across the gaps in SLC-off images (images acquired after the SLC failure). This paper describes the process used to generate the segment model, provides details of the gap-fill algorithm used in deriving the segment-based gap-fill product, and presents the results of the gap-fill process applied to grassland, cropland, and forest landscapes. Our results indicate this product will be useful for a wide variety of applications, including regional-scale studies, general land cover mapping (e.g. forest, urban, and grass), crop-specific mapping and monitoring, and visual assessments. Applications that need to be cautious when using pixels in the gap areas include any applications that require per-pixel accuracy, such as urban characterization or impervious surface mapping, applications that use texture to characterize landscape features, and applications that require accurate measurements of small or narrow landscape features such as roads, farmsteads, and riparian areas.

Genome-Wide Identification, Characterization and Expression Analysis of the Solute Carrier 6 Gene Family in Silkworm (Bombyx mori)

PubMed Central

Tang, Xin; Liu, Huawei; Chen, Quanmei; Wang, Xin; Xiong, Ying; Zhao, Ping

2016-01-01

The solute carrier 6 (SLC6) gene family, initially known as the neurotransmitter transporters, plays vital roles in the regulation of neurotransmitter signaling, nutrient absorption and motor behavior. In this study, a total of 16 candidate genes were identified as SLC6 family gene homologs in the silkworm (Bombyx mori) genome. Spatio-temporal expression patterns of silkworm SLC6 gene transcripts indicated that these genes were highly and specifically expressed in midgut, brain and gonads; moreover, these genes were expressed primarily at the feeding stage or adult stage. Levels of expression for most midgut-specific and midgut-enriched gene transcripts were down-regulated after starvation but up-regulated after re-feeding. In addition, we observed that expression levels of these genes except for BmSLC6-15 and BmGT1 were markedly up-regulated by a juvenile hormone analog. Moreover, brain-enriched genes showed differential expression patterns during wandering and mating processes, suggesting that these genes may be involved in modulating wandering and mating behaviors. Our results improve our understanding of the expression patterns and potential physiological functions of the SLC6 gene family, and provide valuable information for the comprehensive functional analysis of the SLC6 gene family. PMID:27706106

Mesoporous silica-based dosage forms improve bioavailability of poorly soluble drugs in pigs: case example fenofibrate.

PubMed

O'Shea, Joseph P; Nagarsekar, Kalpa; Wieber, Alena; Witt, Vanessa; Herbert, Elisabeth; O'Driscoll, Caitriona M; Saal, Christoph; Lubda, Dieter; Griffin, Brendan T; Dressman, Jennifer B

2017-10-01

Mesoporous silicas (SLC) have demonstrated considerable potential to improve bioavailability of poorly soluble drugs by facilitating rapid dissolution and generating supersaturation. The addition of certain polymers can further enhance the dissolution of these formulations by preventing drug precipitation. This study uses fenofibrate as a model drug to investigate the performance of an SLC-based formulation, delivered with hydroxypropyl methylcellulose acetate succinate (HPMCAS) as a precipitation inhibitor, in pigs. The ability of biorelevant dissolution testing to predict the in vivo performance was also assessed. Fenofibrate-loaded mesoporous silica (FF-SLC), together with HPMCAS, displayed significant improvements in biorelevant dissolution tests relative to a reference formulation consisting of a physical mixture of crystalline fenofibrate with HPMCAS. In vivo assessment in fasted pigs demonstrated bioavailabilities of 86.69 ± 35.37% with combination of FF-SLC and HPMCAS in capsule form and 75.47 ± 14.58% as a suspension, compared to 19.92 ± 9.89% with the reference formulation. A positive correlation was identified between bioavailability and dissolution efficiency. The substantial improvements in bioavailability of fenofibrate from the SLC-based formulations confirm the ability of this formulation strategy to overcome the dissolution and solubility limitations, further raising the prospects of a future commercially available SLC-based formulation. © 2017 Royal Pharmaceutical Society.

Genome-Wide Identification, Characterization and Expression Analysis of the Solute Carrier 6 Gene Family in Silkworm (Bombyx mori).

PubMed

Tang, Xin; Liu, Huawei; Chen, Quanmei; Wang, Xin; Xiong, Ying; Zhao, Ping

2016-10-03

The solute carrier 6 (SLC6) gene family, initially known as the neurotransmitter transporters, plays vital roles in the regulation of neurotransmitter signaling, nutrient absorption and motor behavior. In this study, a total of 16 candidate genes were identified as SLC6 family gene homologs in the silkworm (Bombyx mori) genome. Spatio-temporal expression patterns of silkworm SLC6 gene transcripts indicated that these genes were highly and specifically expressed in midgut, brain and gonads; moreover, these genes were expressed primarily at the feeding stage or adult stage. Levels of expression for most midgut-specific and midgut-enriched gene transcripts were down-regulated after starvation but up-regulated after re-feeding. In addition, we observed that expression levels of these genes except for BmSLC6-15 and BmGT1 were markedly up-regulated by a juvenile hormone analog. Moreover, brain-enriched genes showed differential expression patterns during wandering and mating processes, suggesting that these genes may be involved in modulating wandering and mating behaviors. Our results improve our understanding of the expression patterns and potential physiological functions of the SLC6 gene family, and provide valuable information for the comprehensive functional analysis of the SLC6 gene family.

Involvement of the anion exchanger SLC26A6 in prostaglandin E2- but not forskolin-stimulated duodenal HCO3- secretion.

PubMed

Tuo, Biguang; Riederer, Brigitte; Wang, Zhaohui; Colledge, William H; Soleimani, Manoocher; Seidler, Ursula

2006-02-01

SLC26A6 is a recently identified apical Cl(-)/HCO(3)(-) exchanger with strong expression in murine duodenum. The present study was designed to examine the role of SLC26A6 in prostaglandin E(2) (PGE(2))-, forskolin-, and carbachol-induced duodenal HCO(3)(-) secretion. Murine duodenal mucosal HCO(3)(-) secretion was examined in vitro in Ussing chambers and mucosal SLC26A6 expression levels were analyzed by semiquantitative reverse-transcription polymerase chain reaction. Basal HCO(3)(-) secretion was diminished by 20%, PGE(2)-stimulated HCO(3)(-) secretory response by 59%, and carbachol-stimulated response was reduced by 35% in SLC26A6-/- compared with +/+ duodenal mucosa, whereas the forskolin-stimulated HCO(3)(-) secretory response was not different. In Cl(-)-free solutions, PGE(2)- and carbachol-stimulated HCO(3)(-) secretion was reduced by 81% and 44%, respectively, whereas forskolin-stimulated HCO(3)(-) secretion was not altered significantly. PGE(2) and carbachol, but not forskolin, were able to elicit a Cl(-)-dependent HCO(3)(-) secretory response in the absence of short-circuit current changes in cystic fibrosis transmembrane conductance regulator knockout mice. In murine duodenum, PGE(2)-mediated HCO(3)(-) secretion is strongly SLC26A6 dependent and cystic fibrosis transmembrane conductance regulator independent, whereas forskolin-stimulated HCO(3)(-) secretion is completely SLC26A6 independent and cystic fibrosis transmembrane conductance regulator dependent. Carbachol-induced secretion is less pronounced, but occurs via both transport pathways. This suggests that PGE(2) and forskolin activate distinct HCO(3)(-) transport pathways in the murine duodenum.

Effect of monosaccharide sugars on LH-induced differentiation and sugar transport facilitator (SLC2A) expression in sheep theca cells in vitro.

PubMed

Campbell, B K; Kendall, N R; Onions, V; Guo, L; Scaramuzzi, R J

2014-03-01

The aim of the present study was to investigate the effects of glucose, galactose and fructose on the LH-induced differentiation and mRNA expression of sugar transport facilitators (SLC2A) by sheep thecal cells derived from small antral follicles cultured under serum-free conditions for 6 days. The dose and type of monosaccharide had a significant effect on LH-induced androstenedione production by theca cells and there was a significant interaction (P<0.001). Glucose and galactose were used with equal efficiency so that cell numbers and androstenedione production at the end of the culture were comparable. Pharmacological doses of glucose (16.7 mM) inhibited steroidogenesis (P<0.05). Cell numbers and androstenedione production by cells cultured with fructose were lower than for cells cultured with either glucose or galactose (P<0.001). None of the monosaccharides resulted in the production of lactate. Expression of SLC2A1, SLC2A4 and SLC2A8, but not SLC2A5, mRNA was detected in fresh and cultured theca cells. Large doses (16.7 mM) of glucose and fructose, but not galactose, suppressed (P<0.05) SLC2A expression. The results show that glucose and galactose, but not fructose, are readily metabolised via oxidative pathways to support LH-induced differentiation of sheep theca cells. Further work is required to determine the mechanisms resulting in these differences in relation to the established effects of nutrition on reproductive function.

SLC52A3, A Brown–Vialetto–van Laere syndrome candidate gene is essential for mouse development, but dispensable for motor neuron differentiation

PubMed Central

Intoh, Atsushi; Suzuki, Naoki; Koszka, Kathryn; Eggan, Kevin

2016-01-01

Riboflavin, also known as vitamin B2, is essential for cellular reduction-oxidation reactions, but is not readily synthesized by mammalian cells. It has been proposed that riboflavin absorption occurs through solute carrier family 52 members (SLC52) A1, A2 and A3. These transporters are also candidate genes for the childhood onset-neural degenerative syndrome Brown–Vialetto–Van Laere (BVVL). Although riboflavin is an essential nutrient, why mutations in its transporters result in a neural cell-specific disorder remains unclear. Here, we provide evidence that Slc52a3 is the mouse ortholog of SLC52A3 and show that Slc52a3 deficiency results in early embryonic lethality. Loss of mutant embryos was associated with both defects in placental formation and increased rates of apoptosis in embryonic cells. In contrast, Slc52a3 −/− embryonic stem cell lines could be readily established and differentiated into motor neurons, suggesting that this transporter is dispensable for neural differentiation and short-term maintenance. Consistent with this finding, examination of Slc52a3 gene products in adult tissues revealed expression in the testis and intestine but little or none in the brain and spinal cord. Our results suggest that BVVL patients with SCL52A3 mutations may be good candidates for riboflavin replacement therapy and suggests that either the mutations these individuals carry are hypomorphic, or that in these cases alternative transporters act during human embryogenesis to allow full-term development. PMID:26976849

B0AT2 (SLC6A15) Is Localized to Neurons and Astrocytes, and Is Involved in Mediating the Effect of Leucine in the Brain

PubMed Central

Hägglund, Maria G. A.; Roshanbin, Sahar; Löfqvist, Erik; Hellsten, Sofie V.; Nilsson, Victor C. O.; Todkar, Aniruddha; Zhu, Yinan; Stephansson, Olga; Drgonova, Jana; Uhl, George R.; Schiöth, Helgi B.; Fredriksson, Robert

2013-01-01

The B0AT2 protein is a product of the SLC6A15 gene belonging to the SLC6 subfamily and has been shown to be a transporter of essential branched-chain amino acids. We aimed to further characterize the B0AT2 transporter in CNS, and to use Slc6a15 knock out (KO) mice to investigate whether B0AT2 is important for mediating the anorexigenic effect of leucine. We used the Slc6a15 KO mice to investigate the role of B0AT2 in brain in response to leucine and in particular the effect on food intake. Slc6a15 KO mice show lower reduction of food intake as well as lower neuronal activation in the ventromedial hypothalamic nucleus (VMH) in response to leucine injections compared to wild type mice. We also used RT-PCR on rat tissues, in situ hybridization and immunohistochemistry on mouse CNS tissues to document in detail the distribution of SLC6A15 on gene and protein levels. We showed that B0AT2 immunoreactivity is mainly neuronal, including localization in many GABAergic neurons and spinal cord motor neurons. B0AT2 immunoreactivity was also found in astrocytes close to ventricles, and co-localized with cytokeratin and diazepam binding inhibitor (DBI) in epithelial cells of the choroid plexus. The data suggest that B0AT2 play a role in leucine homeostasis in the brain. PMID:23505546

Adaptation to different salinities exposes functional specialization in the intestine of the sea bream (Sparus aurata L.).

PubMed

Gregório, Sílvia F; Carvalho, Edison S M; Encarnação, Sandra; Wilson, Jonathan M; Power, Deborah M; Canário, Adelino V M; Fuentes, Juan

2013-02-01

The processing of intestinal fluid, in addition to a high drinking rate, is essential for osmoregulation in marine fish. This study analyzed the long-term response of the sea bream (Sparus aurata L.) to relevant changes of external salinity (12, 35 and 55 p.p.t.), focusing on the anterior intestine and in the less-often studied rectum. Intestinal water absorption, epithelial HCO(3)(-) secretion and gene expression of the main molecular mechanisms (SLC26a6, SLC26a3, SLC4a4, atp6v1b, CFTR, NKCC1 and NKCC2) involved in Cl(-) and HCO(3)(-) movements were examined. The anion transporters SLC26a6 and SLC26a3 are expressed severalfold higher in the anterior intestine, while the expression of Atp6v1b (V-type H(+)-ATPase β-subunit) is severalfold higher in the rectum. Prolonged exposure to altered external salinity was without effect on water absorption but was associated with concomitant changes in intestinal fluid content, epithelial HCO(3)(-) secretion and salinity-dependent expression of SLC26a6, SLC26a3 and SLC4a4 in the anterior intestine. However, the most striking response to external salinity was obtained in the rectum, where a 4- to 5-fold increase in water absorption was paralleled by a 2- to 3-fold increase in HCO(3)(-) secretion in response to a salinity of 55 p.p.t. In addition, the rectum of high salinity-acclimated fish shows a sustained (and enhanced) secretory current (I(sc)), identified in vitro in Ussing chambers and confirmed by the higher expression of CFTR and NKCC1 and by immunohistochemical protein localization. Taken together, the present results suggest a functional anterior-posterior specialization with regard to intestinal fluid processing and subsequently to salinity adaptation of the sea bream. The rectum becomes more active at higher salinities and functions as the final controller of intestinal function in osmoregulation.

Common Polymorphisms in the Solute Carrier SLC30A10 are Associated With Blood Manganese and Neurological Function

PubMed Central

Kippler, Maria; Alhamdow, Ayman; Rahman, Syed Moshfiqur; Smith, Donald R.; Vahter, Marie; Lucchini, Roberto G.; Broberg, Karin

2016-01-01

Manganese (Mn) is an essential nutrient in humans, but excessive exposure to Mn may cause neurotoxicity. Despite homeostatic regulation, Mn concentrations in blood vary considerably among individuals. We evaluated if common single-nucleotide polymorphisms (SNPs) in SLC30A10, which likely encodes an Mn transporter, influence blood Mn concentrations and neurological function. We measured blood Mn concentrations by ICP-MS or atomic absorption spectroscopy and genotyped 2 SLC30A10 non-coding SNPs (rs2275707 and rs12064812) by TaqMan PCR in cohorts from Bangladesh (N = 406), the Argentinean Andes (N = 198), and Italy (N = 238). We also measured SLC30A10 expression in whole blood by TaqMan PCR in a sub-group (N = 101) from the Andean cohort, and neurological parameters (sway velocity and finger-tapping speed) in the Italian cohort. The rs2275707 variant allele was associated with increased Mn concentrations in the Andes (8%, P = .027) and Italy (10.6%, P = .012), but not as clear in Bangladesh (3.4%, P = .21; linear regression analysis adjusted for age, gender, and plasma ferritin). This allele was also associated with increased sway velocity (15%, P = .033; adjusted for age and sex) and reduced SLC30A10 expression (−24.6%, P = .029). In contrast, the rs12064812 variant homozygous genotype was associated with reduced Mn concentrations, particularly in the Italian cohort (−18.4%, P = .04), and increased finger-tapping speed (8.7%, P = .025). We show that common SNPs in SLC30A10 are associated with blood Mn concentrations in 3 unrelated cohorts and that their influence may be mediated by altered SLC30A10 expression. Moreover, the SNPs appeared to influence neurological functions independent of blood Mn concentrations, suggesting that SLC30A10 could regulate brain Mn levels. PMID:26628504

Cystinuria Associated with Different SLC7A9 Gene Variants in the Cat

PubMed Central

Raj, Karthik; Osborne, Carl; Giger, Urs

2016-01-01

Cystinuria is a classical inborn error of metabolism characterized by a selective proximal renal tubular defect affecting cystine, ornithine, lysine, and arginine (COLA) reabsorption, which can lead to uroliths and urinary obstruction. In humans, dogs and mice, cystinuria is caused by variants in one of two genes, SLC3A1 and SLC7A9, which encode the rBAT and bo,+AT subunits of the bo,+ basic amino acid transporter system, respectively. In this study, exons and flanking regions of the SLC3A1 and SLC7A9 genes were sequenced from genomic DNA of cats (Felis catus) with COLAuria and cystine calculi. Relative to the Felis catus-6.2 reference genome sequence, DNA sequences from these affected cats revealed 3 unique homozygous SLC7A9 missense variants: one in exon 5 (p.Asp236Asn) from a non-purpose-bred medium-haired cat, one in exon 7 (p.Val294Glu) in a Maine Coon and a Sphinx cat, and one in exon 10 (p.Thr392Met) from a non-purpose-bred long-haired cat. A genotyping assay subsequently identified another cystinuric domestic medium-haired cat that was homozygous for the variant originally identified in the purebred cats. These missense variants result in deleterious amino acid substitutions of highly conserved residues in the bo,+AT protein. A limited population survey supported that the variants found were likely causative. The remaining 2 sequenced domestic short-haired cats had a heterozygous variant at a splice donor site in intron 10 and a homozygous single nucleotide variant at a branchpoint in intron 11 of SLC7A9, respectively. This study identifies the first SLC7A9 variants causing feline cystinuria and reveals that, as in humans and dogs, this disease is genetically heterogeneous in cats. PMID:27404572

Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico

PubMed Central

2014-01-01

Performing genetic studies in multiple human populations can identify disease risk alleles that are common in one population but rare in others1, with the potential to illuminate pathophysiology, health disparities, and the population genetic origins of disease alleles. We analyzed 9.2 million single nucleotide polymorphisms (SNPs) in each of 8,214 Mexicans and Latin Americans: 3,848 with type 2 diabetes (T2D) and 4,366 non-diabetic controls. In addition to replicating previous findings2–4, we identified a novel locus associated with T2D at genome-wide significance spanning the solute carriers SLC16A11 and SLC16A13 (P=3.9×10−13; odds ratio (OR)=1.29). The association was stronger in younger, leaner people with T2D, and replicated in independent samples (P=1.1×10−4; OR=1.20). The risk haplotype carries four amino acid substitutions, all in SLC16A11; it is present at ≈50% frequency in Native American samples and ≈10% in East Asian, but rare in European and African samples. Analysis of an archaic genome sequence indicated the risk haplotype introgressed into modern humans via admixture with Neandertals. The SLC16A11 mRNA is expressed in liver, and V5-tagged SLC16A11 protein localizes to the endoplasmic reticulum. Expression of SLC16A11 in heterologous cells alters lipid metabolism, most notably causing an increase in intracellular triacylglycerol levels. Despite T2D having been well studied by genome-wide association studies (GWAS) in other populations, analysis in Mexican and Latin American individuals identified SLC16A11 as a novel candidate gene for T2D with a possible role in triacylglycerol metabolism. PMID:24390345

Single-layer centrifugation through PureSperm® 80 selects improved quality spermatozoa from frozen-thawed dog semen.

PubMed

Dorado, J; Alcaraz, L; Gálvez, M J; Acha, D; Ortiz, I; Urbano, M; Hidalgo, M

2013-08-01

The aim of this study was to investigate whether single-layer centrifugation (SLC) with PureSperm® 80 could select good quality spermatozoa, including those with specific motility patterns, from doses of frozen dog semen. Semen from 5 dogs was collected and cryopreserved following a standard protocol. After thawing, semen samples were divided into two aliquots: one of them was used as control and the other one processed by SLC. Assessment of sperm motility (assessed by computer-assisted semen analysis), morphology (Diff-Quick staining) and viability (triple fluorescent stain of propidium iodine/isothiocyanate-labeled peanut (Arachis hypogaea) agglutinin/Rhodamine 123), were performed on aliquots of fresh semen, frozen-thawed control and frozen-thawed SLC treated samples. A multivariate clustering procedure separated 26,051 motile spermatozoa into three subpopulations (sP): sP1 consisting of highly active but non-progressive spermatozoa (40.3%), sP2 consisting of spermatozoa with high velocity and progressive motility (30.0%), and sP3 consisting of poorly active and non-progressive spermatozoa (29.7%). SLC with PureSperm® 80 yielded sperm suspensions with improved motility, morphology, viability and acrosome integrity (P<0.001). The frozen-thawed SLC treated samples were enriched in sP2, reaching a proportion of 44.1% of the present spermatozoa. From these results, we concluded that SLC with PureSperm® 80 may be an alternative and successful method for improving the quality of frozen-thawed dog spermatozoa. Moreover, sP2 (high-speed and progressive spermatozoa) was more frequently observed after SLC. Finally, this study also demonstrated that the general motile sperm structure present in dogs remained constant despite the effect caused by either cryopreservation or separation by SLC through PureSperm® 80. Copyright © 2013 Elsevier B.V. All rights reserved.

Effects of fasting and refeeding on gene expression of slc15a1a, a gene encoding an oligopeptide transporter (PepT1), in the intestine of Mozambique tilapia.

PubMed

Orozco, Zenith Gaye A; Soma, Satoshi; Kaneko, Toyoji; Watanabe, Soichi

2017-01-01

The tissue distribution of slc15a1a, a gene that encodes an oligopeptide transporter, PepT1, and its response to fasting and refeeding were investigated in the intestinal epithelium of Mozambique tilapia for a better understanding of its role on nutrient absorption. The slc15a1a was predominantly expressed in the absorptive epithelia of the anterior part of the intestine, suggesting that digested oligopeptides are primarily absorbed in the anterior intestine. The response of slc15a1a to fasting was evaluated at 1, 2, 4, 7 and 14days after the last feeding. Fasting revealed a biphasic effect, where short-term fasting significantly upregulated slc15a1a expression and long-term fasting resulted in downregulation. The expression level continued to decrease and fell below the pre-fasted level from day 4 to 14. Proximal (the hepatic loop, HL) and distal parts (the proximal major coil, PMC) of the anterior intestine showed different magnitudes of responses to fasting; slc15a1a expression in the PMC showed greater upregulation and downregulation than that in the HL. Refeeding significantly stimulated slc15a1a expression at day 3, although the expression did not exceed the pre-fasted level. Observed responses of slc15a1a to fasting and refeeding suggest that the expression level of this gene can serve as a sensitive indicator of the changes that may occur in altering nutritional conditions. These findings contribute to a better understanding of the role of PepT1 in nutrition and of the complex mechanisms underlying the absorption of oligopeptides and amino acids in the intestine, and may lead to development of possible means to manipulate the absorption processes for the improvement of growth and other metabolic and physiological conditions in fish. Copyright © 2016. Published by Elsevier Inc.

Searching for dark photon with positrons at Jefferson lab

NASA Astrophysics Data System (ADS)

Marsicano, Luca

2018-05-01

The interest in the Dark Photon (A' or U) has recently grown, since it could act as a light mediator to a new sector of Dark Matter particles. In this paradigm, the electron-positron annihilation can rarely produce a γA' pair. Various experiments (e.g. PADME@LNF [1], VEPP-3 [2]) have been proposed to detect this process using positron beams impinging on fixed targets. In such experiments, the energy of the photon from the e+e-→ γA' process is measured with an electromagnetic calorimeter and the missing mass is computed (the A' interacts weakly with Standard Model matter so it can't be detected). However, the A' mass range that can be explored with this technique is limited by the accessible energy in the center of mass frame, which goes as the square root of the beam energy. The realization of a 11 GeV positron beam at Jefferson Lab would allow to search for A' masses up to ˜ 100 MeV, reaching unexplored regions of the A' parameter space. A preliminary study on the feasibility of a PADME-like experiment at Jefferson Lab has been carried out, assuming a 11 GeV positron beam with a ˜ 100 nA current. The achievable sensitivity was estimated, studying the main sources of background (positron bremsstrahlung, annihilation into 2 gammas) using CALCHEP [3] and GEANT4 [4] simulations.

Stimulation of the amino acid transporter SLC6A19 by JAK2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bhavsar, Shefalee K.; Hosseinzadeh, Zohreh; Merches, Katja

Highlights: Black-Right-Pointing-Pointer The amino acid transporter SLC6A19 is upregulated by Janus kinase-2 JAK2. Black-Right-Pointing-Pointer The {sup V617F}JAK2 mutant, causing myeloproliferative disease, is more effective. Black-Right-Pointing-Pointer JAK2 inhibitor AG490 reverses stimulation of SLC6A19 by {sup V617F}JAK2. Black-Right-Pointing-Pointer JAK2 enhances SLC6A19 protein insertion into the cell membrane. Black-Right-Pointing-Pointer SLC6A19 may contribute to amino acid uptake into {sup V617F}JAK2 expressing tumor cells. -- Abstract: JAK2 (Janus kinase-2) is expressed in a wide variety of cells including tumor cells and contributes to the proliferation and survival of those cells. The gain of function mutation {sup V617F}JAK2 mutant is found in the majority of myeloproliferativemore » diseases. Cell proliferation depends on the availability of amino acids. Concentrative cellular amino acid uptake is in part accomplished by Na{sup +} coupled amino acid transport through SLC6A19 (B(0)AT). The present study thus explored whether JAK2 activates SLC6A19. To this end, SLC6A19 was expressed in Xenopus oocytes with or without wild type JAK2, {sup V617F}JAK2 or inactive {sup K882E}JAK2 and electrogenic amino acid transport determined by dual electrode voltage clamp. In SLC6A19-expressing oocytes but not in oocytes injected with water or JAK2 alone, the addition of leucine (2 mM) to the bath generated a current (I{sub le}), which was significantly increased following coexpression of JAK2 or {sup V617F}JAK2, but not by coexpression of {sup K882E}JAK2. Coexpression of JAK2 enhanced the maximal transport rate without significantly modifying the affinity of the carrier. Exposure of the oocytes to the JAK2 inhibitor AG490 (40 {mu}M) resulted in a gradual decline of I{sub le}. According to chemiluminescence JAK2 enhanced the carrier protein abundance in the cell membrane. The decline of I{sub le} following inhibition of carrier insertion by brefeldin A (5 {mu}M) was similar in the absence and presence of JAK2 indicating that JAK2 stimulates carrier insertion into rather than inhibiting carrier retrival from the cell membrane. In conclusion, JAK2 up-regulates SLC6A19 activity which may foster amino acid uptake into JAK2 expressing cells.« less

Age-dependent oxidation of extracellular cysteine/cystine redox state (Eh(Cys/CySS)) in mouse lung fibroblasts is mediated by a decline in Slc7a11 expression.

PubMed

Zheng, Yuxuan; Ritzenthaler, Jeffrey D; Burke, Tom J; Otero, Javier; Roman, Jesse; Watson, Walter H

2018-04-01

Aging is associated with progressive oxidation of the extracellular environment. The redox state of human plasma, defined by the concentrations of cysteine (Cys) and cystine (CySS), becomes more oxidized as we age. Recently, we showed that fibroblasts isolated from the lungs of young and old mice retain this differential phenotype; old cells produce and maintain a more oxidizing extracellular redox potential (E h (Cys/CySS)) than young cells. Microarray analysis identified down-regulation of Slc7a11, the light subunit of the CySS/glutamate transporter, as a potential mediator of age-related oxidation in these cells. The purpose of the present study was to investigate the mechanistic link between Slc7a11 expression and extracellular E h (Cys/CySS). Sulforaphane treatment or overexpression of Slc7a11 was used to increase Slc7a11 in lung fibroblasts from old mice, and sulfasalazine treatment or siRNA-mediated knock down was used to decrease Slc7a11 in young fibroblasts. Slc7a11 mRNA levels were measured by real-time PCR, Slc7a11 activity was determined by measuring the rate of glutamate release, Cys, CySS, glutathione (GSH) and its disulfide (GSSG) were measured by HPLC, and E h (Cys/CySS) was calculated from the Nernst equation. The results showed that both E h (Cys/CySS) and E h (GSH/GSSG) were more oxidized in the conditioned media of old cells than in young cells. Up-regulation of Slc7a11 via overexpression or sulforaphane treatment restored extracellular E h (Cys/CySS) in cultures of old cells, whereas down-regulation reproduced the oxidizing E h (Cys/CySS) in young cells. Only sulforaphane treatment was able to increase total GSH and restore E h (GSH/GSSG), whereas overexpression, knock down and sulfasalazine had no effect on these parameters. In addition, inhibition of GSH synthesis with buthionine sulfoximine had no effect on the ability of cells to restore their extracellular redox potential in response to an oxidative challenge. In conclusion, our study reveals Slc7a11 is the key regulator of age-dependent changes in extracellular E h (Cys/CySS) in primary mouse lung fibroblasts, and its effects are not dependent on GSH synthesis. Copyright © 2018 Elsevier Inc. All rights reserved.

Mutation analysis of SLC26A4 (Pendrin) gene in a Brazilian sample of hearing-impaired subjects.

PubMed

Nonose, Renata Watanabe; Lezirovitz, Karina; de Mello Auricchio, Maria Teresa Balester; Batissoco, Ana Carla; Yamamoto, Guilherme Lopes; Mingroni-Netto, Regina Célia

2018-05-08

Mutations in the SLC26A4 gene are associated with Pendred syndrome and autosomal recessive non-syndromic deafness (DFNB4). Both disorders have similar audiologic characteristics: bilateral hearing loss, often severe or profound, which may be associated with abnormalities of the inner ear, such as dilatation of the vestibular aqueduct or Mondini dysplasia. But, in Pendred syndrome (OMIM #274600), with autosomal recessive inheritance, besides congenital sensorineural deafness, goiter or thyroid dysfunctions are frequently present. The aim of this study was to determine whether mutations in SLC26A4 are a frequent cause of hereditary deafness in Brazilian patients. Microsatellite haplotypes linked to SLC26A4 were investigated in 68 families presenting autosomal recessive non-syndromic deafness. In the probands of the 16 families presenting segregation consistent with linkage to SLC26A4, Sanger sequencing of the 20 coding exons was performed. In an additional sample of 15 individuals with suspected Pendred syndrome, because of the presence of hypothyroidism or cochleovestibular malformations, the SLC26A4 gene coding region was also sequenced. In two of the 16 families with indication of linkage to SLC26A4, the probands were found to be compound heterozygotes for probably pathogenic different mutations: three novel (c.1003 T > G (p. F335 V), c.1553G > A (p.W518X), c.2235 + 2 T > C (IVS19 + 2 T > C), and one already described, c.84C > A (p.S28R). Two of the 15 individuals with suspected Pendred syndrome because of hypothyreoidism or cochleovestibular malformations were monoallelic for likely pathogenic mutations: a splice mutation (IVS7 + 2 T > C) and the previously described c.1246A > C (p.T416P). Pathogenic copy number variations were excluded in the monoallelic cases and in those with normal results after Sanger sequencing. Additional mutations in the SLC26A4 gene or other definite molecular cause for deafness were not identified in the monoallelic patients, after exome sequencing. Biallelic pathogenic mutations in SLC26A4 explained ~ 3% of cases selected because of autosomal recessive deafness. Monoallelic mutations were present in ~ 13% of isolated cases of deafness with cochleovestibular malformations or suspected Pendred syndrome. These data reinforce the importance of mutation screening of SLC26A4 in Brazilian subjects and highlight the elevated frequency of monoallelic patients.

Monte Carlo dose calculations in homogeneous media and at interfaces: a comparison between GEPTS, EGSnrc, MCNP, and measurements.

PubMed

Chibani, Omar; Li, X Allen

2002-05-01

Three Monte Carlo photon/electron transport codes (GEPTS, EGSnrc, and MCNP) are bench-marked against dose measurements in homogeneous (both low- and high-Z) media as well as at interfaces. A brief overview on physical models used by each code for photon and electron (positron) transport is given. Absolute calorimetric dose measurements for 0.5 and 1 MeV electron beams incident on homogeneous and multilayer media are compared with the predictions of the three codes. Comparison with dose measurements in two-layer media exposed to a 60Co gamma source is also performed. In addition, comparisons between the codes (including the EGS4 code) are done for (a) 0.05 to 10 MeV electron beams and positron point sources in lead, (b) high-energy photons (10 and 20 MeV) irradiating a multilayer phantom (water/steel/air), and (c) simulation of a 90Sr/90Y brachytherapy source. A good agreement is observed between the calorimetric electron dose measurements and predictions of GEPTS and EGSnrc in both homogeneous and multilayer media. MCNP outputs are found to be dependent on the energy-indexing method (Default/ITS style). This dependence is significant in homogeneous media as well as at interfaces. MCNP(ITS) fits more closely the experimental data than MCNP(DEF), except for the case of Be. At low energy (0.05 and 0.1 MeV), MCNP(ITS) dose distributions in lead show higher maximums in comparison with GEPTS and EGSnrc. EGS4 produces too penetrating electron-dose distributions in high-Z media, especially at low energy (<0.1 MeV). For positrons, differences between GEPTS and EGSnrc are observed in lead because GEPTS distinguishes positrons from electrons for both elastic multiple scattering and bremsstrahlung emission models. For the 60Co source, a quite good agreement between calculations and measurements is observed with regards to the experimental uncertainty. For the other cases (10 and 20 MeV photon sources and the 90Sr/90Y beta source), a good agreement is found between the three codes. In conclusion, differences between GEPTS and EGSnrc results are found to be very small for almost all media and energies studied. MCNP results depend significantly on the electron energy-indexing method.

Differential Regulation of Thyroid Hormone Metabolism Target Genes during Non-thyroidal Illness Syndrome Triggered by Fasting or Sepsis in Adult Mice

PubMed Central

Fontes, Klaus N.; Cabanelas, Adriana; Bloise, Flavia F.; de Andrade, Cherley Borba Vieira; Souza, Luana L.; Wilieman, Marianna; Trevenzoli, Isis H.; Agra, Lais C.; Silva, Johnatas D.; Bandeira-Melo, Christianne; Silva, Pedro L.; Rocco, Patricia R. M.; Ortiga-Carvalho, Tania M.

2017-01-01

Fasting and sepsis induce profound changes in thyroid hormone (TH) central and peripheral metabolism. These changes affect TH action and are called the non-thyroidal illness syndrome (NTIS). To date, it is still debated whether NTIS represents an adaptive response or a real hypothyroid state at the tissue level. Moreover, even though it has been considered the same syndrome, we hypothesized that fasting and sepsis induce a distinct set of changes in thyroid hormone metabolism. Herein, we aimed to evaluate the central and peripheral expression of genes involved in the transport (MCT8/Slc16a2 and MCT10/Slc16a10), metabolism (Dio1, Dio2, and Dio3) and action (Thra and Thrb) of TH during NTIS induced by fasting or sepsis. Male mice were subjected to a 48 h period of fasting or cecal ligation and puncture (CLP)-induced sepsis. At the peripheral level, fasting led to: (1) reduced serum thyroxine (T4) and triiodothyronine (T3), expression of Dio1, Thra, Slc16a2, and MCT8 protein in liver; (2) increased hepatic Slc16a10 and Dio3 expression; and (3) decreased Slc16a2 and Slc16a10 expressions in the thyroid gland. Fasting resulted in reduction of Tshb expression in the pituitary and increased expression of Dio2 in total hypothalamus, arcuate (ARC) and paraventricular (PVN) nucleus. CLP induced sepsis resulted in reduced: (1) T4 serum levels; (2) Dio1, Slc16a2, Slc16a10, Thra, and Thrb expression in liver as well as Slc16a2 expression in the thyroid gland (3) Thrb and Tshb mRNA expression in the pituitary; (4) total leukocyte counts in the bone marrow while increased its number in peritoneal and pleural fluids. In summary, fasting- or sepsis-driven NTIS promotes changes in the set point of hypothalamus-pituitary-thyroid axis through different mechanisms. Reduced hepatic THRs expression in conjunction with reduced TH transporters expression in the thyroid gland may indicate, respectively, reduction in the peripheral action and in the secretion of TH, which may contribute to the low TH serum levels observed in both models. PMID:29118715

Differential Regulation of Thyroid Hormone Metabolism Target Genes during Non-thyoidal Illness Syndrome Triggered by Fasting or Sepsis in Adult Mice.

PubMed

Fontes, Klaus N; Cabanelas, Adriana; Bloise, Flavia F; de Andrade, Cherley Borba Vieira; Souza, Luana L; Wilieman, Marianna; Trevenzoli, Isis H; Agra, Lais C; Silva, Johnatas D; Bandeira-Melo, Christianne; Silva, Pedro L; Rocco, Patricia R M; Ortiga-Carvalho, Tania M

2017-01-01

Fasting and sepsis induce profound changes in thyroid hormone (TH) central and peripheral metabolism. These changes affect TH action and are called the non-thyroidal illness syndrome (NTIS). To date, it is still debated whether NTIS represents an adaptive response or a real hypothyroid state at the tissue level. Moreover, even though it has been considered the same syndrome, we hypothesized that fasting and sepsis induce a distinct set of changes in thyroid hormone metabolism. Herein, we aimed to evaluate the central and peripheral expression of genes involved in the transport (MCT8/ Slc16a2 and MCT10/ Slc16a10 ), metabolism ( Dio1, Dio2 , and Dio3 ) and action ( Thra and Thrb ) of TH during NTIS induced by fasting or sepsis. Male mice were subjected to a 48 h period of fasting or cecal ligation and puncture (CLP)-induced sepsis. At the peripheral level, fasting led to: (1) reduced serum thyroxine (T 4 ) and triiodothyronine (T 3 ), expression of Dio1, Thra, Slc16a2 , and MCT8 protein in liver; (2) increased hepatic Slc16a10 and Dio3 expression; and (3) decreased Slc16a2 and Slc16a10 expressions in the thyroid gland. Fasting resulted in reduction of Tshb expression in the pituitary and increased expression of Dio2 in total hypothalamus, arcuate (ARC) and paraventricular (PVN) nucleus. CLP induced sepsis resulted in reduced: (1) T 4 serum levels; (2) Dio1, Slc16a2, Slc16a10, Thra , and Thrb expression in liver as well as Slc16a2 expression in the thyroid gland (3) Thrb and Tshb mRNA expression in the pituitary; (4) total leukocyte counts in the bone marrow while increased its number in peritoneal and pleural fluids. In summary, fasting- or sepsis-driven NTIS promotes changes in the set point of hypothalamus-pituitary-thyroid axis through different mechanisms. Reduced hepatic THRs expression in conjunction with reduced TH transporters expression in the thyroid gland may indicate, respectively, reduction in the peripheral action and in the secretion of TH, which may contribute to the low TH serum levels observed in both models.

Cloning and characterization of the promoter regions from the parent and paralogous creatine transporter genes.

PubMed

Ndika, Joseph D T; Lusink, Vera; Beaubrun, Claudine; Kanhai, Warsha; Martinez-Munoz, Cristina; Jakobs, Cornelis; Salomons, Gajja S

2014-01-10

Interconversion between phosphocreatine and creatine, catalyzed by creatine kinase is crucial in the supply of ATP to tissues with high energy demand. Creatine's importance has been established by its use as an ergogenic aid in sport, as well as the development of intellectual disability in patients with congenital creatine deficiency. Creatine biosynthesis is complemented by dietary creatine uptake. Intracellular transport of creatine is carried out by a creatine transporter protein (CT1/CRT/CRTR) encoded by the SLC6A8 gene. Most tissues express this gene, with highest levels detected in skeletal muscle and kidney. There are lower levels of the gene detected in colon, brain, heart, testis and prostate. The mechanism(s) by which this regulation occurs is still poorly understood. A duplicated unprocessed pseudogene of SLC6A8-SLC6A10P has been mapped to chromosome 16p11.2 (contains the entire SLC6A8 gene, plus 2293 bp of 5'flanking sequence and its entire 3'UTR). Expression of SLC6A10P has so far only been shown in human testis and brain. It is still unclear as to what is the function of SLC6A10P. In a patient with autism, a chromosomal breakpoint that intersects the 5'flanking region of SLC6A10P was identified; suggesting that SLC6A10P is a non-coding RNA involved in autism. Our aim was to investigate the presence of cis-acting factor(s) that regulate expression of the creatine transporter, as well as to determine if these factors are functionally conserved upstream of the creatine transporter pseudogene. Via gene-specific PCR, cloning and functional luciferase assays we identified a 1104 bp sequence proximal to the mRNA start site of the SLC6A8 gene with promoter activity in five cell types. The corresponding 5'flanking sequence (1050 bp) on the pseudogene also had promoter activity in all 5 cell lines. Surprisingly the pseudogene promoter was stronger than that of its parent gene in 4 of the cell lines tested. To the best of our knowledge, this is the first experimental evidence of a pseudogene with stronger promoter activity than its parental gene. © 2013.

NIS expression in thyroid tumors, relation with prognosis clinicopathological and molecular features

PubMed Central

Tavares, Catarina; Coelho, Maria João; Eloy, Catarina; Melo, Miguel; da Rocha, Adriana Gaspar; Pestana, Ana; Batista, Rui; Ferreira, Luciana Bueno; Rios, Elisabete; Selmi-Ruby, Samia; Cavadas, Bruno; Pereira, Luísa; Sobrinho Simões, Manuel

2018-01-01

Thyroid cancer therapy is based on surgery followed by radioiodine treatment. The incorporation of radioiodine by cancer cells is mediated by sodium iodide symporter (NIS) (codified by the SLC5A5 gene), that is functional only when targeted to the cell membrane. We aimed to evaluate if NIS expression in thyroid primary tumors would be helpful in predicting tumor behavior, response to therapy and prognosis. NIS expression was addressed by qPCR and immunohistochemistry. In order to validate our data, we also studied SLC5A5 expression on 378 primary papillary thyroid carcinomas from The Cancer Genome Atlas (TCGA) database. In our series, SLC5A5 expression was lower in carcinomas with vascular invasion and with extrathyroidal extension and in those harboring BRAFV600E mutation. Analysis of SLC5A5 expression from TCGA database confirmed our results. Furthermore, it showed that larger tumors, with locoregional recurrences and/or distant metastases or harboring RAS, BRAF and/or TERT promoter (TERTp) mutations presented significantly less SLC5A5 expression. Regarding immunohistochemistry, 12/211 of the cases demonstrated NIS in the membrane of tumor cells, those cases showed variable outcomes concerning therapy success, prognosis and all but one were wild type for BRAF, NRAS and TERTp mutations. SLC5A5 mRNA lower expression is associated with features of aggressiveness and with key genetic alterations involving BRAF, RAS and TERTp. Mutations in these genes seem to decrease protein expression and its targeting to the cell membrane. SLC5A5 mRNA expression is more informative than NIS immunohistochemical expression regarding tumor aggressiveness and prognostic features. PMID:29298843

Adverse early life experience and social stress during adulthood interact to increase serotonin transporter mRNA expression

PubMed Central

Gardner, Katherine L.; Hale, Matthew W.; Lightman, Stafford L.; Plotsky, Paul M.; Lowry, Christopher A.

2009-01-01

Anxiety disorders, depression and animal models of vulnerability to a depression-like syndrome have been associated with dysregulation of serotonergic systems in the brain. To evaluate the effects of early life experience, adverse experiences during adulthood, and potential interactions between these factors on serotonin transporter (slc6a4) mRNA expression, we investigated in rats the effects of maternal separation (180 min/day from days 2–14 of life; MS180), neonatal handing (15 min/day from days 2–14 of life; MS15), or normal animal facility rearing control conditions (AFR) with or without subsequent exposure to adult social defeat on slc6a4 mRNA expression in the dorsal raphe nucleus (DR) and caudal linear nucleus. At the level of specific subdivisions of the DR, there were no differences in slc6a4 mRNA expression between MS15 and AFR rats. Among rats exposed to a novel cage control condition, increased slc6a4 mRNA expression was observed in the dorsal part of the DR in MS180 rats, relative to AFR control rats. In contrast, MS180 rats exposed to social defeat as adults had increased slc6a4 mRNA expression throughout the DR compared to both MS15 and AFR controls. Social defeat increased slc6a4 mRNA expression, but only in MS180 rats and only in the “lateral wings” of the DR. Overall these data demonstrate that early life experience and stressful experience during adulthood interact to determine slc6a4 mRNA expression. These data support the hypothesis that early life experience and major stressful life events contribute to dysregulation of serotonergic systems in stress-related neuropsychiatric disorders. PMID:19781533

Generation of a Slc39a8 hypomorph mouse: Markedly decreased ZIP8 Zn{sup 2+}/(HCO{sub 3}{sup -}){sub 2} transporter expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Bin; He, Lei; Dong, Hongbin

2011-07-01

Highlights: {yields} The mouse Slc39a8 gene encodes the ZIP8 transporter. {yields} ZIP8 functions endogenously as a electroneutral Zn{sup 2+}/(HCO{sub 3}{sup -}){sub 2} symporter. {yields} A Slc39a8(neo/neo) hypomorph mouse, due to retention of the neo mini-gene, has been created. {yields} ZIP8 expression in utero is {approx}90% decreased in all tissues examined. {yields} This mouse model will be useful for studying developmental and in utero physiological functions of ZIP8. -- Abstract: Previously this laboratory has identified the mouse Slc39a8 gene encoding the ZIP8 transporter, important in cadmium uptake. ZIP8 functions endogenously as a electroneutral Zn{sup 2+}/(HCO{sub 3}{sup -}){sub 2} symporter, moving bothmore » ions into the cell. The overall physiological importance of ZIP8 remains unclear. Herein we describe generation of a mouse line carrying the Slc39a8(neo) allele, containing the Frt-flanked neomycin-resistance (neo) mini-cassette in intron 3 and loxP sites in introns 3 and 6. Cre recombinase functions correctly in Escherichia coli and in adeno-Cre-infected mouse fetal fibroblasts, but does not function in the intact mouse for reasons not clear. Slc39a8(neo) is a hypomorphic allele, because Slc39a8(neo/neo) homozygotes exhibit dramatically decreased ZIP8 expression in embryo, fetus, and visceral yolk sac - in comparison to their littermate wild-type controls. This ZIP8 hypomorph will be instrumental in studying developmental and in utero physiological functions of the ZIP8 transporter.« less

SLC9A9 Co-expression modules in autism-associated brain regions.

PubMed

Patak, Jameson; Hess, Jonathan L; Zhang-James, Yanli; Glatt, Stephen J; Faraone, Stephen V

2017-03-01

SLC9A9 is a sodium hydrogen exchanger present in the recycling endosome and highly expressed in the brain. It is implicated in neuropsychiatric disorders, including autism spectrum disorders (ASDs). Little research concerning its gene expression patterns and biological pathways has been conducted. We sought to investigate its possible biological roles in autism-associated brain regions throughout development. We conducted a weighted gene co-expression network analysis on RNA-seq data downloaded from Brainspan. We compared prenatal and postnatal gene expression networks for three ASD-associated brain regions known to have high SLC9A9 gene expression. We also performed an ASD-associated single nucleotide polymorphism enrichment analysis and a cell signature enrichment analysis. The modules showed differences in gene constituents (membership), gene number, and connectivity throughout time. SLC9A9 was highly associated with immune system functions, metabolism, apoptosis, endocytosis, and signaling cascades. Gene list comparison with co-immunoprecipitation data was significant for multiple modules. We found a disproportionately high autism risk signal among genes constituting the prenatal hippocampal module. The modules were enriched with astrocyte and oligodendrocyte markers. SLC9A9 is potentially involved in the pathophysiology of ASDs. Our investigation confirmed proposed functions for SLC9A9, such as endocytosis and immune regulation, while also revealing potential roles in mTOR signaling and cell survival.. By providing a concise molecular map and interactions, evidence of cell type and implicated brain regions we hope this will guide future research on SLC9A9. Autism Res 2017, 10: 414-429. © 2016 International Society for Autism Research, Wiley Periodicals, Inc. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

SLC6A19 is a novel putative gene, induced by dioxins via AhR in human hepatoma HepG2 cells.

PubMed

Tian, Wenjing; Fu, Hualing; Xu, Tuan; Xu, Sherry Li; Guo, Zhiling; Tian, Jijing; Tao, Wuqun; Xie, Heidi Qunhui; Zhao, Bin

2018-06-01

The aryl hydrocarbon receptor (AhR) plays an important role in mediating dioxins toxicity. Currently, genes of P450 families are major research interests in studies on AhR-mediated gene alterations caused by dioxins. Genes related to other metabolic pathways or processes may be also responsive to dioxin exposures. Amino acid transporter B0AT1 (encoded by SLC6A19) plays a decisive role in neutral amino acid transport which is present in kidney, intestine and liver. However, effects of dioxins on its expression are still unknown. In the present study, we focused on the effects of dioxin and dioxin-like compounds on SLC6A19 expression in HepG2 cells. We identified SLC6A19 as a novel putative target gene of AhR activation in HepG2 cells. 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) increased the expression of SLC6A19 in time- and concentration-dependent manners. Using AhR antagonist CH223191 and/or siRNA assays, we demonstrated that certain AhR agonists upregulated SLC6A19 expression via AhR, including TCDD, 1,2,3,7,8-pentachlorodibenzo-p-dioxin (1,2,3,7,8-PeCDD), 2,3,4,7,8- pentachlorodibenzofuran (2,3,4,7,8-PeCDF) and PCB126. In addition, the expression of B0AT1 was also significantly induced by TCDD in HepG2 cells. Our study suggested that dioxins might affect the transcription and translation of SLC6A19 in HepG2 cells, which might be a novel putative gene to assess dioxins' toxicity in amino acid transport and metabolism in liver. Copyright © 2018 Elsevier Ltd. All rights reserved.

Supplementation of soybean lecithin-based semen extender by antioxidants: complementary flowcytometric study on post-thawed ram spermatozoa.

PubMed

Sharafi, Mohsen; Zhandi, Mahdi; Akbari Sharif, Abbas

2015-06-01

The purpose of the current study was to evaluate the effects of cysteine (C) and glutathione (G) on the post-thawed ram sperm quality. Collected semen samples from four mature rams were diluted with five soybean lecithin (SL)-based extenders containing: no antioxidant (SL-0), 5 mM cysteine (SL-C5), 10 mM cysteine (SL-C10), 5 mM glutathione (SL-G5) and 10 mM glutathione (SL-G10). After freeze-thawing process, motion and velocity parameters, plasma membrane integrity and functionality, morphological abnormality, lipid peroxidation, acrosomal status, mitochondria activity, and apoptosis status of post-thawed ram spermatozoa were assessed. The results showed that SL-C10 increased the total motility and plasma membrane integrity (p < 0.05) of post-thawed ram spermatozoa (55.86 ± 1.37 and 60.57 ± 1.34 %) compared to other extenders. Progressive motility was significantly higher in SL-C10 (24.71 ± 1.13 %) compared to SL-0 (20 ± 1.13 %) and SL-G10 (15 ± 1.13 %). Mitochondrial activity was significantly higher in SL-C10 (56.83 ± 2.29 %) compared to SL-G10 (38.75 ± 2.29 %). Capacitation and acrosomal status, lipid peroxidation, and the percentage of dead spermatozoa were not affected by different extenders. The percentage of live spermatozoa was higher in SL-C10 (56.33 ± 1.35 %) compared to other extenders. Also, SL-C10 resulted in a lower percentage of apoptotic spermatozoa (14.17 ± 0.53 %) compared to other extenders. The results of this study showed that supplementation of SL-based ram semen extender with 10 mM cysteine resulted in an improved quality of post-thawed ram spermatozoa.

Commercial Slit-Lamp Anterior Segment Photography versus Digital Compact Camera Mounted on a Standard Slit-Lamp with an Adapter.

PubMed

Oliphant, Huw; Kennedy, Alasdair; Comyn, Oliver; Spalton, David J; Nanavaty, Mayank A

2018-06-16

To compare slit lamp mounted cameras (SLC) versus digital compact camera (DCC) with slit-lamp adaptor when used by an inexperienced technician. In this cross sectional study, where posterior capsule opacification (PCO) was used as a comparator, patients were consented for one photograph with SLC and two with DCC (DCC1 and DCC2), with a slit-lamp adaptor. An inexperienced clinic technician, who took all the photographs and masked the images, recruited one eye of each patient. Images were graded for PCO using ECPO2000 software by two independent masked graders. Repeatability between DCC1 & DCC2 and limits-of-agreement between SLC and DCC1 mounted on slit-lamp with an adaptor were assessed. Coefficient-of-repeatability and Bland-Altmann plots were analyzed. Seventy-two patients (eyes) were recruited in the study. First 9 patients (eyes) were excluded due to unsatisfactory image quality from both the systems. Mean EPCO score for SLC was 2.28 (95% CI: 2.09 -2.45), for DCC1 was 2.28 (95% CI: 2.11-2.45), and for the DCC2 was 2.11 (95% CI: 2.11-2.45). There was no significant difference in EPCO scores between SLC Vs. DCC1 (p = 0.98) and between DCC1 and DCC 2 (p = 0.97). Coefficient of repeatability between DCC images was 0.42, and the coefficient of repeatability between DCC and SLC was 0.58. DCC on slit-lamp with an adaptor is comparable to a SLC. There is an initial learning curve, which is similar for both for an inexperienced person. This opens up the possibility for low cost anterior segment imaging in the clinical, research and teaching settings.

Interaction between the SLC19A1 gene and maternal first trimester fever on offspring neural tube defects.

PubMed

Pei, Lijun; Zhu, Huiping; Ye, Rongwei; Wu, Jilei; Liu, Jianmeng; Ren, Aiguo; Li, Zhiwen; Zheng, Xiaoying

2015-01-01

Many studies have indicated that the reduced folate carrier gene (SLC19A1) is associated with an increased risk of neural tube defects (NTDs). However, the interaction between the SLC19A1 gene variant and maternal fever exposure and NTD risk remains unknown. The aim of this study was to investigate whether the risk for NTDs was influenced by the interactions between the SLC19A1 (rs1051266) variant and maternal first trimester fever. We investigated the potential interaction between maternal first trimester fever and maternal or offspring SLC19A1 polymorphism through a population-based case-control study. One hundred and four nuclear families with NTDs and 100 control families with nonmal newborns were included in the study. SLC19A1 polymorphism was determined using polymerase chain reaction-restricted fragment length polymorphism. Mothers who had the GG/GA genotype and first trimester fever had an elevated risk of NTDs (adjusted odds ratio, 11.73; 95% confidence interval, 3.02-45.58) as compared to absence of maternal first trimester fever and AA genotype after adjusting for maternal education, paternal education, and age, and had a significant interactive coefficient (γ = 3.17) between maternal GG/GA genotype and first trimester fever. However, there was no interaction between offspring's GG/GA genotype and maternal first trimester fever (the interactive coefficient γ = 0.97) after adjusting for confounding factors. Our findings suggested that the risk of NTDs was potentially influenced by a gene-environment interaction between maternal SLC19A1 rs1051266 GG/GA genotype and first trimester fever. Maternal GG/GA genotype may strengthen the effect of maternal fever exposure on NTD risk in this Chinese population. © 2014 Wiley Periodicals, Inc.

Population-specific influence of SLC2A9 genotype on the acute hyperuricaemic response to a fructose load.

PubMed

Dalbeth, Nicola; House, Meaghan E; Gamble, Gregory D; Horne, Anne; Pool, Bregina; Purvis, Lauren; Stewart, Angela; Merriman, Marilyn; Cadzow, Murray; Phipps-Green, Amanda; Merriman, Tony R

2013-11-01

SLC2A9 is a strong genetic risk factor for hyperuricaemia and gout. SLC2A9 (GLUT9) is a high capacity urate transporter and reportedly transports glucose and fructose. Intake of fructose-containing beverages is associated with development of hyperuricaemia and gout. To determine whether genetic variation in SLC2A9 influences the acute serum urate response to a fructose load. Following an overnight fast, 76 healthy volunteers (25 Māori, 26 Pacific, 25 European Caucasian) drank a solution containing 64 g fructose. Serum and urine were obtained immediately before and then 30, 60, 120 and 180 min after ingestion. The SLC2A9 single nucleotide polymorphism (SNP) rs11942223 was genotyped and data were analysed based on the presence or absence of the gout protective minor allele (C). The rs11942223 C allele was present in 17 participants (22%). In the entire group, fructose intake led to an increase in serum urate, which peaked 60 min following fructose ingestion (analysis of variance p=0.006). The presence of the C allele was associated with an attenuated hyperuricaemic response (p(SNP)<0.0001) and increased fractional excretion of uric acid (FEUA) (p(SNP)<0.0001) following the fructose load. The effects of rs11942223 variants on serum urate and FEUA in response to fructose were present only in Caucasian ancestral subgroups but not in the Māori and Pacific ancestral subgroup. Variation in SLC2A9 influences acute serum urate and FEUA responses to a fructose load. SLC2A9 genotype may influence the development of gout on exposure to fructose-containing beverages, particularly in European Caucasian populations.

SLC25A13 Gene Analysis in Citrin Deficiency: Sixteen Novel Mutations in East Asian Patients, and the Mutation Distribution in a Large Pediatric Cohort in China

PubMed Central

Song, Yuan-Zong; Zhang, Zhan-Hui; Lin, Wei-Xia; Zhao, Xin-Jing; Deng, Mei; Ma, Yan-Li; Guo, Li; Chen, Feng-Ping; Long, Xiao-Ling; He, Xiang-Ling; Sunada, Yoshihide; Soneda, Shun; Nakatomi, Akiko; Dateki, Sumito; Ngu, Lock-Hock; Kobayashi, Keiko; Saheki, Takeyori

2013-01-01

Background The human SLC25A13 gene encodes citrin, the liver-type mitochondrial aspartate/glutamate carrier isoform 2 (AGC2), and SLC25A13 mutations cause citrin deficiency (CD), a disease entity that encompasses different age-dependant clinical phenotypes such as Adult-onset Citrullinemia Type II (CTLN2) and Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency (NICCD). The analyses of SLC25A13 gene and its protein/mRNA products remain reliable tools for the definitive diagnoses of CD patients, and so far, the SLC25A13 mutation spectrum in Chinese CD patients has not been well-characterized yet. Methods and Results By means of direct DNA sequencing, cDNA cloning and SNP analyses, 16 novel pathogenic mutations, including 9 missense, 4 nonsense, 1 splice-site, 1 deletion and 1 large transposal insertion IVS4ins6kb (GenBank accession number KF425758), were identified in CTLN2 or NICCD patients from China, Japan and Malaysia, respectively, making the SLC25A13 variations worldwide reach the total number of 81. A large NICCD cohort of 116 Chinese cases was also established, and the 4 high-frequency mutations contributed a much larger proportion of the mutated alleles in the patients from south China than in those from the north (χ2 = 14.93, P<0.01), with the latitude of 30°N as the geographic dividing line in mainland China. Conclusions This paper further enriched the SLC25A13 variation spectrum worldwide, and formed a substantial contribution to the in-depth understanding of the genotypic feature of Chinese CD patients. PMID:24069319

Differential cystine and dibasic amino acid handling after loss of function of the amino acid transporter b0,+AT (Slc7a9) in mice.

PubMed

Di Giacopo, Andrea; Rubio-Aliaga, Isabel; Cantone, Alessandra; Artunc, Ferruh; Rexhepaj, Rexhep; Frey-Wagner, Isabelle; Font-Llitjós, Mariona; Gehring, Nicole; Stange, Gerti; Jaenecke, Isabel; Mohebbi, Nilufar; Closs, Ellen I; Palacín, Manuel; Nunes, Virginia; Daniel, Hannelore; Lang, Florian; Capasso, Giovambattista; Wagner, Carsten A

2013-12-15

Cystinuria is an autosomal recessive disease caused by mutations in SLC3A1 (rBAT) and SLC7A9 (b(0,+)AT). Gene targeting of the catalytic subunit (Slc7a9) in mice leads to excessive excretion of cystine, lysine, arginine, and ornithine. Here, we studied this non-type I cystinuria mouse model using gene expression analysis, Western blotting, clearance, and brush-border membrane vesicle (BBMV) uptake experiments to further characterize the renal and intestinal consequences of losing Slc7a9 function. The electrogenic and BBMV flux studies in the intestine suggested that arginine and ornithine are transported via other routes apart from system b(0,+). No remarkable gene expression changes were observed in other amino acid transporters and the peptide transporters in the intestine and kidney. Furthermore, the glomerular filtration rate (GFR) was reduced by 30% in knockout animals compared with wild-type animals. The fractional excretion of arginine was increased as expected (∼100%), but fractional excretions of lysine (∼35%), ornithine (∼16%), and cystine (∼11%) were less affected. Loss of function of b(0,+)AT reduced transport of cystine and arginine in renal BBMVs and completely abolished the exchanger activity of dibasic amino acids with neutral amino acids. In conclusion, loss of Slc7a9 function decreases the GFR and increases the excretion of several amino acids to a lesser extent than expected with no clear regulation at the mRNA and protein level of alternative transporters and no increased renal epithelial uptake. These observations indicate that transporters located in distal segments of the kidney and/or metabolic pathways may partially compensate for Slc7a9 loss of function.

De Novo Mutations in SLC25A24 Cause a Disorder Characterized by Early Aging, Bone Dysplasia, Characteristic Face, and Early Demise.

PubMed

Writzl, Karin; Maver, Ales; Kovačič, Lidija; Martinez-Valero, Paula; Contreras, Laura; Satrustegui, Jorgina; Castori, Marco; Faivre, Laurence; Lapunzina, Pablo; van Kuilenburg, André B P; Radović, Slobodanka; Thauvin-Robinet, Christel; Peterlin, Borut; Del Arco, Araceli; Hennekam, Raoul C

2017-11-02

A series of simplex cases have been reported under various diagnoses sharing early aging, especially evident in congenitally decreased subcutaneous fat tissue and sparse hair, bone dysplasia of the skull and fingers, a distinctive facial gestalt, and prenatal and postnatal growth retardation. For historical reasons, we suggest naming the entity Fontaine syndrome. Exome sequencing of four unrelated affected individuals showed that all carried the de novo missense variant c.649C>T (p.Arg217Cys) or c.650G>A (p.Arg217His) in SLC25A24, a solute carrier 25 family member coding for calcium-binding mitochondrial carrier protein (SCaMC-1, also known as SLC25A24). SLC25A24 allows an electro-neutral and reversible exchange of ATP-Mg and phosphate between the cytosol and mitochondria, which is required for maintaining optimal adenine nucleotide levels in the mitochondrial matrix. Molecular dynamic simulation studies predict that p.Arg217Cys and p.Arg217His narrow the substrate cavity of the protein and disrupt transporter dynamics. SLC25A24-mutant fibroblasts and cells expressing p.Arg217Cys or p.Arg217His variants showed altered mitochondrial morphology, a decreased proliferation rate, increased mitochondrial membrane potential, and decreased ATP-linked mitochondrial oxygen consumption. The results suggest that the SLC25A24 mutations lead to impaired mitochondrial ATP synthesis and cause hyperpolarization and increased proton leak in association with an impaired energy metabolism. Our findings identify SLC25A24 mutations affecting codon 217 as the underlying genetic cause of human progeroid Fontaine syndrome. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Examining the Role of Components of Slc11a1 (Nramp1) in the Susceptibility of New Zealand Sea Lions (Phocarctos hookeri) to Disease

PubMed Central

Osborne, Amy J.; Pearson, John; Chilvers, B. Louise; Kennedy, Martin A.; Gemmell, Neil J.

2015-01-01

The New Zealand sea lion (NZSL, Phocarctos hookeri) is a Threatened marine mammal with a restricted distribution and a small, declining, population size. The species is susceptible to bacterial pathogens, having suffered three mass mortality events since 1998. Understanding the genetic factors linked to this susceptibility is important in mitigating population decline. The gene solute carrier family 11 member a1 (Slc11a1) plays an important role in mammalian resistance or susceptibility to a wide range of bacterial pathogens. At present, Slc11a1 has not been characterised in many taxa, and despite its known roles in mediating the effects of infectious disease agents, has not been examined as a candidate gene in susceptibility or resistance in any wild population of conservation concern. Here we examine components of Slc11a1 in NZSLs and identify: i) a polymorphic nucleotide in the promoter region; ii) putative shared transcription factor binding motifs between canids and NZSLs; and iii) a conserved polymorphic microsatellite in the first intron of Slc11a1, which together suggest conservation of Slc11a1 gene structure in otariids. At the promoter polymorphism, we demonstrate a shift away from normal allele frequency distributions and an increased likelihood of death from infectious causes with one allelic variant. While this increased likelihood is not statistically significant, lack of significance is potentially due to the complexity of genetic susceptibility to disease in wild populations. Our preliminary data highlight the potential significance of this gene in disease resistance in wild populations; further exploration of Slc11a1 will aid the understanding of susceptibility to infection in mammalian species of conservation significance. PMID:25874773

Functional analysis of mutations in SLC7A9, and genotype-phenotype correlation in non-Type I cystinuria.

PubMed

Font, M A; Feliubadaló, L; Estivill, X; Nunes, V; Golomb, E; Kreiss, Y; Pras, E; Bisceglia, L; d'Adamo, A P; Zelante, L; Gasparini, P; Bassi, M T; George , A L; Manzoni, M; Riboni, M; Ballabio, A; Borsani, G; Reig, N; Fernández, E; Zorzano, A; Bertran, J; Palacín, M

2001-02-15

Cystinuria (OMIM 220100) is a common recessive disorder of renal reabsorption of cystine and dibasic amino acids that results in nephrolithiasis of cystine. Mutations in SLC3A1, which encodes rBAT, cause Type I cystinuria, and mutations in SLC7A9, which encodes a putative subunit of rBAT (b(o,+)AT), cause non-Type I cystinuria. Here we describe the genomic structure of SLC7A9 (13 exons) and 28 new mutations in this gene that, together with the seven previously reported, explain 79% of the alleles in 61 non-Type I cystinuria patients. These data demonstrate that SLC7A9 is the main non-Type I cystinuria gene. Mutations G105R, V170M, A182T and R333W are the most frequent SLC7A9 missense mutations found. Among heterozygotes carrying these mutations, A182T heterozygotes showed the lowest urinary excretion values of cystine and dibasic amino acids. Functional analysis of mutation A182T after co-expression with rBAT in HeLa cells revealed significant residual transport activity. In contrast, mutations G105R, V170M and R333W are associated to a complete or almost complete loss of transport activity, leading to a more severe urinary phenotype in heterozygotes. SLC7A9 mutations located in the putative transmembrane domains of b(o,+)AT and affecting conserved amino acid residues with a small side chain generate a severe phenotype, while mutations in non-conserved residues give rise to a mild phenotype. These data provide the first genotype-phenotype correlation in non-Type I cystinuria, and show that a mild urinary phenotype in heterozygotes may associate with mutations with significant residual transport activity.

De Novo Mutations in SLC25A24 Cause a Craniosynostosis Syndrome with Hypertrichosis, Progeroid Appearance, and Mitochondrial Dysfunction.

PubMed

Ehmke, Nadja; Graul-Neumann, Luitgard; Smorag, Lukasz; Koenig, Rainer; Segebrecht, Lara; Magoulas, Pilar; Scaglia, Fernando; Kilic, Esra; Hennig, Anna F; Adolphs, Nicolai; Saha, Namrata; Fauler, Beatrix; Kalscheuer, Vera M; Hennig, Friederike; Altmüller, Janine; Netzer, Christian; Thiele, Holger; Nürnberg, Peter; Yigit, Gökhan; Jäger, Marten; Hecht, Jochen; Krüger, Ulrike; Mielke, Thorsten; Krawitz, Peter M; Horn, Denise; Schuelke, Markus; Mundlos, Stefan; Bacino, Carlos A; Bonnen, Penelope E; Wollnik, Bernd; Fischer-Zirnsak, Björn; Kornak, Uwe

2017-11-02

Gorlin-Chaudhry-Moss syndrome (GCMS) is a dysmorphic syndrome characterized by coronal craniosynostosis and severe midface hypoplasia, body and facial hypertrichosis, microphthalmia, short stature, and short distal phalanges. Variable lipoatrophy and cutis laxa are the basis for a progeroid appearance. Using exome and genome sequencing, we identified the recurrent de novo mutations c.650G>A (p.Arg217His) and c.649C>T (p.Arg217Cys) in SLC25A24 in five unrelated girls diagnosed with GCMS. Two of the girls had pronounced neonatal progeroid features and were initially diagnosed with Wiedemann-Rautenstrauch syndrome. SLC25A24 encodes a mitochondrial inner membrane ATP-Mg/P i carrier. In fibroblasts from affected individuals, the mutated SLC25A24 showed normal stability. In contrast to control cells, the probands' cells showed mitochondrial swelling, which was exacerbated upon treatment with hydrogen peroxide (H 2 O 2 ). The same effect was observed after overexpression of the mutant cDNA. Under normal culture conditions, the mitochondrial membrane potential of the probands' fibroblasts was intact, whereas ATP content in the mitochondrial matrix was lower than that in control cells. However, upon H 2 O 2 exposure, the membrane potential was significantly elevated in cells harboring the mutated SLC25A24. No reduction of mitochondrial DNA copy number was observed. These findings demonstrate that mitochondrial dysfunction with increased sensitivity to oxidative stress is due to the SLC25A24 mutations. Our results suggest that the SLC25A24 mutations induce a gain of pathological function and link mitochondrial ATP-Mg/P i transport to the development of skeletal and connective tissue. Copyright © 2017 American Society of Human Genetics. All rights reserved.

Survey of beam instrumentation used in SLC

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ecklund, S.D.

A survey of beam instruments used at SLAC in the SLC machine is presented. The basic utility and operation of each device is briefly described. The various beam instruments used at the Stanford Linear Collider (SLC), can be classified by the function they perform. Beam intensity, position and size are typical of the parameters of beam which are measured. Each type of parameter is important for adjusting or tuning the machine in order to achieve optimum performance. 39 refs.

Quantifying the relative contributions of different solute carriers to aggregate substrate transport

PubMed Central

Taslimifar, Mehdi; Oparija, Lalita; Verrey, Francois; Kurtcuoglu, Vartan; Olgac, Ufuk; Makrides, Victoria

2017-01-01

Determining the contributions of different transporter species to overall cellular transport is fundamental for understanding the physiological regulation of solutes. We calculated the relative activities of Solute Carrier (SLC) transporters using the Michaelis-Menten equation and global fitting to estimate the normalized maximum transport rate for each transporter (Vmax). Data input were the normalized measured uptake of the essential neutral amino acid (AA) L-leucine (Leu) from concentration-dependence assays performed using Xenopus laevis oocytes. Our methodology was verified by calculating Leu and L-phenylalanine (Phe) data in the presence of competitive substrates and/or inhibitors. Among 9 potentially expressed endogenous X. laevis oocyte Leu transporter species, activities of only the uniporters SLC43A2/LAT4 (and/or SLC43A1/LAT3) and the sodium symporter SLC6A19/B0AT1 were required to account for total uptake. Furthermore, Leu and Phe uptake by heterologously expressed human SLC6A14/ATB0,+ and SLC43A2/LAT4 was accurately calculated. This versatile systems biology approach is useful for analyses where the kinetics of each active protein species can be represented by the Hill equation. Furthermore, its applicable even in the absence of protein expression data. It could potentially be applied, for example, to quantify drug transporter activities in target cells to improve specificity. PMID:28091567

Haplotypes in SLC24A5 Gene as Ancestry Informative Markers in Different Populations

PubMed Central

Giardina, Emiliano; Pietrangeli, Ilenia; Martínez-Labarga, Cristina; Martone, Claudia; de Angelis, Flavio; Spinella, Aldo; De Stefano, Gianfranco; Rickards, Olga; Novelli, Giuseppe

2008-01-01

Ancestry informative markers (AIMs) are human polymorphisms that exhibit substantially allele frequency differences among populations. These markers can be useful to provide information about ancestry of samples which may be useful in predicting a perpetrator’s ethnic origin to aid criminal investigations. Variations in human pigmentation are the most obvious phenotypes to distinguish individuals. It has been recently shown that the variation of a G in an A allele of the coding single-nucleotide polymorphism (SNP) rs1426654 within SLC24A5 gene varies in frequency among several population samples according to skin pigmentation. Because of these observations, the SLC24A5 locus has been evaluated as Ancestry Informative Region (AIR) by typing rs1426654 together with two additional intragenic markers (rs2555364 and rs16960620) in 471 unrelated individuals originating from three different continents (Africa, Asia and Europe). This study further supports the role of human SLC24A5 gene in skin pigmentation suggesting that variations in SLC24A5 haplotypes can correlate with human migration and ancestry. Furthermore, our data do reveal the utility of haplotype and combined unphased genotype analysis of SLC24A5 in predicting ancestry and provide a good example of usefulness of genetic characterization of larger regions, in addition to single polymorphisms, as candidates for population-specific sweeps in the ancestral population. PMID:19440451

Could Hypoxia increase the prevalence of thrombotic complications in Polycythemia Vera?

PubMed Central

Zangari, Maurizio; Tolomelli, Giulia; Lee, Jasmine CH; Stein, Brady L.; Hickman, Kimberly; Swierczek, Sabina; Kelley, Todd W.; Berno, Tamara; Moliterno, Alison R.; Spivak, Jerry L.; Gordeuk, Victor R.; Prchal, Josef

2013-01-01

Background Thromboses represent a major cause of morbidity and mortality in Polycythemia Vera (PV) but the contributing mechanisms are not fully described. Patients and methods To evaluate whether environmental conditions such as altitude/hypoxia could impact thromboses history, we retrospectively analyzed thrombosis history in 71 PV patients living at an elevation of 5,000 feet or more in the SLC area (SLC) and 166 PV patients living near sea level in the Baltimore area (BLM). The SLC cohort was older with a longer disease duration. No significant differences in type of anticoagulation therapy or prothrombotic factors were present between the two cohorts. After adjusting for age, sex and disease duration, SLC patients experienced an estimated 3.9-fold increase in the odds of a history of thromboses compared to BLM patients (95% confidence interval 1.8-7.6; p = 0.0004). A history of cardiovascular event was present in 58% of the SLC patients compared to 27% of the BLM patients (p<0.0001). Before diagnosis thromboses occurred in 18% and 4% of the SLC and BLM groups respectively (p =0.003). No correlation between JAK2V617F allele burden and thrombosis was observed in this study. Conclusion This retrospective study suggests that even moderate hypoxia associated with 5,000 feet elevation should be considered as independent prothrombotic risk factor. This observation needs to be confirmed by prospective studies. PMID:23392352

Human SLC26A1 gene variants: a pilot study.

PubMed

Dawson, Paul A; Sim, Pearl; Mudge, David W; Cowley, David

2013-01-01

Kidney stones are a global health problem, incurring massive health costs annually. Why stones recur in many patients remains unknown but likely involves environmental, physiological, and genetic factors. The solute linked carrier (SLC) 26A1 gene has previously been linked to kidney stones in mice. SLC26A1 encodes the sulfate anion transporter 1 (SAT1) protein, and its loss in mice leads to hyperoxaluria and calcium oxalate renal stones. To investigate the possible involvement of SAT1 in human urolithiasis, we screened the SLC26A1 gene in a cohort of 13 individuals with recurrent calcium oxalate urolithiasis, which is the commonest type. DNA sequence analyses showed missense mutations in seven patients: one individual was heterozygous R372H; 4 individuals were heterozygous Q556R; one patient was homozygous Q556R; and one patient with severe nephrocalcinosis (requiring nephrectomy) was homozygous Q556R and heterozygous M132T. The M132 amino acid in human SAT1 is conserved with 15 other species and is located within the third transmembrane domain of the predicted SAT1 protein structure, suggesting that this amino acid may be important for SAT1 function. These initial findings demonstrate genetic variants in SLC26A1 of recurrent stone formers and warrant wider independent studies of SLC26A1 in humans with recurrent calcium oxalate stones.

A novel non-sense mutation in the SLC2A10 gene of an arterial tortuosity syndrome patient of Kurdish origin.

PubMed

Zaidi, Syed H E; Meyer, Sascha; Peltekova, Vanya D; Lindinger, Angelika; Teebi, Ahmad S; Faiyaz-Ul-Haque, Muhammad

2009-07-01

Arterial tortuosity syndrome (ATS) is a rare autosomal recessive disorder in which patients display tortuosity of arteries in addition to hyperextensible skin, joint laxity, and other connective tissue features. This syndrome is caused by mutations in the SLC2A10 gene. In this article we describe an ATS girl of Kurdish origin who, in addition to arterial tortuosity and connective tissue features, displays stomach displacement within the thorax and bilateral hip dislocation. Clinical details of this patient have been reported previously. Sequencing of the SLC2A10 gene identified a novel homozygous non-sense c.756C>A mutation in this patient's DNA. This mutation in the SLC2A10 gene replaces a cysteine encoding codon with a stop signal. This is believed to cause a premature truncation of GLUT10 protein in this patient. We conclude that patients of Kurdish origin who display arterial tortuosity associated with skin hyperextensibility, joint hypermobility, and characteristic facial features may carry mutations in the SLC2A10 gene.

Involvement of the Neutral Amino Acid Transporter SLC6A15 and Leucine in Obesity-Related Phenotypes

PubMed Central

Drgonova, Jana; Jacobsson, Josefin A.; Han, Joan C.; Yanovski, Jack A.; Fredriksson, Robert; Marcus, Claude; Schiöth, Helgi B.; Uhl, George R.

2013-01-01

Brain pathways, including those in hypothalamus and nucleus of the solitary tract, influence food intake, nutrient preferences, metabolism and development of obesity in ways that often differ between males and females. Branched chain amino acids, including leucine, can suppress food intake, alter metabolism and change vulnerability to obesity. The SLC6A15 (v7-3) gene encodes a sodium-dependent transporter of leucine and other branched chain amino acids that is expressed by neurons in hypothalamus and nucleus of the solitary tract. We now report that SLC6A15 knockout attenuates leucine's abilities to reduce both: a) intake of normal chow and b) weight gain produced by access to a high fat diet in gender-selective fashions. We identify SNPs in the human SLC6A15 that are associated with body mass index and insulin resistance in males. These observations in mice and humans support a novel, gender-selective role for brain amino acid compartmentalization mediated by SLC6A15 in diet and obesity-associated phenotypes. PMID:24023709

Knockdown of SLC41A1 magnesium transporter promotes mineralization and attenuates magnesium inhibition during osteogenesis of mesenchymal stromal cells.

PubMed

Tsao, Yu-Tzu; Shih, Ya-Yi; Liu, Yu-An; Liu, Yi-Shiuan; Lee, Oscar K

2017-02-21

Magnesium is essential for numerous physiological functions. Magnesium exists mostly in bone and the amount is dynamically regulated by skeletal remodeling. Accelerating bone mass loss occurs when magnesium intake is insufficient; whereas high magnesium could lead to mineralization defects. However, the underlying magnesium regulatory mechanisms remain elusive. In the present study, we investigated the effects of high extracellular magnesium concentration on osteogenic differentiation of mesenchymal stromal/stem cells (MSCs) and the role of magnesium transporter SLC41A1 in the mineralization process. Murine MSCs derived from the bone marrow of BALB/c mouse or commercially purchased human MSCs were treated with osteogenic induction medium containing 5.8 mM magnesium chloride and the osteogenic differentiation efficiency was compared with that of MSCs in normal differentiation medium containing 0.8 mM magnesium chloride by cell morphology, gene expression profile of osteogenic markers, and Alizarin Red staining. Slc41a1 gene knockdown in MSCs was performed by siRNA transfection using Lipofectamine RNAiMAX, and the differentiation efficiency of siRNA-treated MSCs was also assessed. High concentration of extracellular magnesium ion inhibited mineralization during osteogenic differentiation of MSCs. Early osteogenic marker genes including osterix, alkaline phosphatase, and type I collagen were significantly downregulated in MSCs under high concentration of magnesium, whereas late marker genes such as osteopontin, osteocalcin, and bone morphogenetic protein 2 were upregulated with statistical significance compared with those in normal differentiation medium containing 0.8 mM magnesium. siRNA treatment targeting SLC41A1 magnesium transporter, a member of the solute carrier family with a predominant Mg 2+ efflux system, accelerated the mineralization process and ameliorated the inhibition of mineralization caused by high concentration of magnesium. High concentration of magnesium significantly upregulated Dkk1 gene expression and the upregulation was attenuated after the Slc41a1 gene was knocked down. Immunofluorescent staining showed that Slc41a1 gene knockdown promoted the translocation of phosphorylated β-catenin into nuclei. In addition, secreted MGP protein was elevated after Slc41a1 was knocked down. High concentration of extracellular magnesium modulates gene expression of MSCs during osteogenic differentiation and inhibits the mineralization process. Additionally, we identified magnesium transporter SLC41A1 that regulates the interaction of magnesium and MSCs during osteogenic differentiation. Wnt signaling is suggested to be involved in SLC41A1-mediated regulation. Tissue-specific SLC41A1 could be a potential treatment for bone mass loss; in addition, caution should be taken regarding the role of magnesium in osteoporosis and the design of magnesium alloys for implantation.

Proteomics of Skin Proteins in Psoriasis: From Discovery and Verification in a Mouse Model to Confirmation in Humans*

PubMed Central

Lundberg, Kathleen C.; Fritz, Yi; Johnston, Andrew; Foster, Alexander M.; Baliwag, Jaymie; Gudjonsson, Johann E.; Schlatzer, Daniela; Gokulrangan, Giridharan; McCormick, Thomas S.; Chance, Mark R.; Ward, Nicole L.

2015-01-01

Herein, we demonstrate the efficacy of an unbiased proteomics screening approach for studying protein expression changes in the KC-Tie2 psoriasis mouse model, identifying multiple protein expression changes in the mouse and validating these changes in human psoriasis. KC-Tie2 mouse skin samples (n = 3) were compared with littermate controls (n = 3) using gel-based fractionation followed by label-free protein expression analysis. 5482 peptides mapping to 1281 proteins were identified and quantitated: 105 proteins exhibited fold-changes ≥2.0 including: stefin A1 (average fold change of 342.4 and an average p = 0.0082; cystatin A, human ortholog); slc25a5 (average fold change of 46.2 and an average p = 0.0318); serpinb3b (average fold change of 35.6 and an average p = 0.0345; serpinB1, human ortholog); and kallikrein related peptidase 6 (average fold change of 4.7 and an average p = 0.2474; KLK6). We independently confirmed mouse gene expression-based increases of selected genes including serpinb3b (17.4-fold, p < 0.0001), KLK6 (9-fold, p = 0.002), stefin A1 (7.3-fold; p < 0.001), and slc25A5 (1.5-fold; p = 0.05) using qRT-PCR on a second cohort of animals (n = 8). Parallel LC/MS/MS analyses on these same samples verified protein-level increases of 1.3-fold (slc25a5; p < 0.05), 29,000-fold (stefinA1; p < 0.01), 322-fold (KLK6; p < 0.0001) between KC-Tie2 and control mice. To underscore the utility and translatability of our combined approach, we analyzed gene and protein expression levels in psoriasis patient skin and primary keratinocytes versus healthy controls. Increases in gene expression for slc25a5 (1.8-fold), cystatin A (3-fold), KLK6 (5.8-fold), and serpinB1 (76-fold; all p < 0.05) were observed between healthy controls and involved lesional psoriasis skin and primary psoriasis keratinocytes. Moreover, slc25a5, cystatin A, KLK6, and serpinB1 protein were all increased in lesional psoriasis skin compared with normal skin. These results highlight the usefulness of preclinical disease models using readily-available mouse skin and demonstrate the utility of proteomic approaches for identifying novel peptides/proteins that are differentially regulated in psoriasis that could serve as sources of auto-antigens or provide novel therapeutic targets for the development of new anti-psoriatic treatments. PMID:25351201

DAΦNE operation with electron-cloud-clearing electrodes.

PubMed

Alesini, D; Drago, A; Gallo, A; Guiducci, S; Milardi, C; Stella, A; Zobov, M; De Santis, S; Demma, T; Raimondi, P

2013-03-22

The effects of an electron cloud (e-cloud) on beam dynamics are one of the major factors limiting performances of high intensity positron, proton, and ion storage rings. In the electron-positron collider DAΦNE, namely, a horizontal beam instability due to the electron-cloud effect has been identified as one of the main limitations on the maximum stored positron beam current and as a source of beam quality deterioration. During the last machine shutdown in order to mitigate such instability, special electrodes have been inserted in all dipole and wiggler magnets of the positron ring. It has been the first installation all over the world of this type since long metallic electrodes have been installed in all arcs of the collider positron ring and are currently used during the machine operation in collision. This has allowed a number of unprecedented measurements (e-cloud instabilities growth rate, transverse beam size variation, tune shifts along the bunch train) where the e-cloud contribution is clearly evidenced by turning the electrodes on and off. In this Letter we briefly describe a novel design of the electrodes, while the main focus is on experimental measurements. Here we report all results that clearly indicate the effectiveness of the electrodes for e-cloud suppression.

ZnO Luminescence and scintillation studied via photoexcitation, X-ray excitation, and gamma-induced positron spectroscopy.

PubMed

Ji, J; Colosimo, A M; Anwand, W; Boatner, L A; Wagner, A; Stepanov, P S; Trinh, T T; Liedke, M O; Krause-Rehberg, R; Cowan, T E; Selim, F A

2016-08-23

The luminescence and scintillation properties of ZnO single crystals were studied by photoluminescence and X-ray-induced luminescence (XRIL) techniques. XRIL allowed a direct comparison to be made between the near-band emission (NBE) and trap emissions providing insight into the carrier recombination efficiency in the ZnO crystals. It also provided bulk luminescence measurements that were not affected by surface states. The origin of a green emission, the dominant trap emission in ZnO, was then investigated by gamma-induced positron spectroscopy (GIPS) - a unique defect spectroscopy method that enables positron lifetime measurements to be made for a sample without contributions from positron annihilation in the source materials. The measurements showed a single positron decay curve with a 175 ps lifetime component that was attributed to Zn vacancies passivated by hydrogen. Both oxygen vacancies and hydrogen-decorated Zn vacancies were suggested to contribute to the green emission. By combining scintillation measurements with XRIL, the fast scintillation in ZnO crystals was found to be strongly correlated with the ratio between the defect luminescence and NBE. This study reports the first application of GIPS to semiconductors, and it reveals the great benefits of the XRIL technique for the study of emission and scintillation properties of materials.

ZnO Luminescence and scintillation studied via photoexcitation, X-ray excitation, and gamma-induced positron spectroscopy

NASA Astrophysics Data System (ADS)

Ji, J.; Colosimo, A. M.; Anwand, W.; Boatner, L. A.; Wagner, A.; Stepanov, P. S.; Trinh, T. T.; Liedke, M. O.; Krause-Rehberg, R.; Cowan, T. E.; Selim, F. A.

2016-08-01

The luminescence and scintillation properties of ZnO single crystals were studied by photoluminescence and X-ray-induced luminescence (XRIL) techniques. XRIL allowed a direct comparison to be made between the near-band emission (NBE) and trap emissions providing insight into the carrier recombination efficiency in the ZnO crystals. It also provided bulk luminescence measurements that were not affected by surface states. The origin of a green emission, the dominant trap emission in ZnO, was then investigated by gamma-induced positron spectroscopy (GIPS) - a unique defect spectroscopy method that enables positron lifetime measurements to be made for a sample without contributions from positron annihilation in the source materials. The measurements showed a single positron decay curve with a 175 ps lifetime component that was attributed to Zn vacancies passivated by hydrogen. Both oxygen vacancies and hydrogen-decorated Zn vacancies were suggested to contribute to the green emission. By combining scintillation measurements with XRIL, the fast scintillation in ZnO crystals was found to be strongly correlated with the ratio between the defect luminescence and NBE. This study reports the first application of GIPS to semiconductors, and it reveals the great benefits of the XRIL technique for the study of emission and scintillation properties of materials.

ZnO Luminescence and scintillation studied via photoexcitation, X-ray excitation, and gamma-induced positron spectroscopy

PubMed Central

Ji, J.; Colosimo, A. M.; Anwand, W.; Boatner, L. A.; Wagner, A.; Stepanov, P. S.; Trinh, T. T.; Liedke, M. O.; Krause-Rehberg, R.; Cowan, T. E.; Selim, F. A.

2016-01-01

The luminescence and scintillation properties of ZnO single crystals were studied by photoluminescence and X-ray-induced luminescence (XRIL) techniques. XRIL allowed a direct comparison to be made between the near-band emission (NBE) and trap emissions providing insight into the carrier recombination efficiency in the ZnO crystals. It also provided bulk luminescence measurements that were not affected by surface states. The origin of a green emission, the dominant trap emission in ZnO, was then investigated by gamma-induced positron spectroscopy (GIPS) - a unique defect spectroscopy method that enables positron lifetime measurements to be made for a sample without contributions from positron annihilation in the source materials. The measurements showed a single positron decay curve with a 175 ps lifetime component that was attributed to Zn vacancies passivated by hydrogen. Both oxygen vacancies and hydrogen-decorated Zn vacancies were suggested to contribute to the green emission. By combining scintillation measurements with XRIL, the fast scintillation in ZnO crystals was found to be strongly correlated with the ratio between the defect luminescence and NBE. This study reports the first application of GIPS to semiconductors, and it reveals the great benefits of the XRIL technique for the study of emission and scintillation properties of materials. PMID:27550235

On the use of positron counting for radio-Assay in nuclear pharmaceutical production.

PubMed

Maneuski, D; Giacomelli, F; Lemaire, C; Pimlott, S; Plenevaux, A; Owens, J; O'Shea, V; Luxen, A

2017-07-01

Current techniques for the measurement of radioactivity at various points during PET radiopharmaceutical production and R&D are based on the detection of the annihilation gamma rays from the radionuclide in the labelled compound. The detection systems to measure these gamma rays are usually variations of NaI or CsF scintillation based systems requiring costly and heavy lead shielding to reduce background noise. These detectors inherently suffer from low detection efficiency, high background noise and very poor linearity. They are also unable to provide any reasonably useful position information. A novel positron counting technique is proposed for the radioactivity assay during radiopharmaceutical manufacturing that overcomes these limitations. Detection of positrons instead of gammas offers an unprecedented level of position resolution of the radiation source (down to sub-mm) thanks to the nature of the positron interaction with matter. Counting capability instead of charge integration in the detector brings the sensitivity down to the statistical limits at the same time as offering very high dynamic range and linearity from zero to any arbitrarily high activity. This paper reports on a quantitative comparison between conventional detector systems and the proposed positron counting detector. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Magnetic measurements of the 10 T superconducting wiggler for the SPring-8 storage ring

NASA Astrophysics Data System (ADS)

Batrakov, A.; Borovikov, V.; Bekhtenev, E.; Fedurin, M.; Hara, M.; Karpov, G.; Kuzin, M.; Mezentsev, N.; Miahara, Y.; Shimada, T.; Shkaruba, V.; Soutome, K.; Tzumaki, K.

2001-07-01

In 1999, in the frame of the project ISTC #767 "Budker INP/RIKEN Slow Positron Source", the Budker Institute of Nuclear Physics had made a 10 T Three-pole Superconducting Wiggler. The wiggler will be the keystone of this project by its installation on the SPring-8 storage ring for powerful gamma ray generation ( λ c=450 keV ), that will be used for slow positron production ( Nγ( ɛ>1 MeV)˜10 15, γ/s I e=0.1 A ). A. Ando et al., Proposal of the high magnetic field super conducting WLS for slow positron source at SPring-8, presented at SR1 '97 Conference. In January, 2000, the wiggler was transported to SPring-8, where the last test and measurements were carried out in collaboration with Japan. In this article, the results of measurements of the magnetic field, finding the magnetic field amplitude by an NMR probe, the definition of feed current relations by stretch current wire method, the calibration of a Hall probe in the high magnetic field, and the measurement of the magnetic field profile by a Hall probe are presented.

Evidence for epistasis between SLC6A4 and ITGB3 in autism etiology and in the determination of platelet serotonin levels.

PubMed

Coutinho, Ana M; Sousa, Inês; Martins, Madalena; Correia, Catarina; Morgadinho, Teresa; Bento, Celeste; Marques, Carla; Ataíde, Assunção; Miguel, Teresa S; Moore, Jason H; Oliveira, Guiomar; Vicente, Astrid M

2007-04-01

Autism is a neurodevelopmental disorder of unclear etiology. The consistent finding of platelet hyperserotonemia in a proportion of patients and its heritability within affected families suggest that genes involved in the serotonin system play a role in this disorder. The role in autism etiology of seven candidate genes in the serotonin metabolic and neurotransmission pathways and mapping to autism linkage regions (SLC6A4, HTR1A, HTR1D, HTR2A, HTR5A, TPH1 and ITGB3) was analyzed in a sample of 186 nuclear families. The impact of interactions among these genes in autism was assessed using the multifactor-dimensionality reduction (MDR) method in 186 patients and 181 controls. We further evaluated whether the effect of specific gene variants or gene interactions associated with autism etiology might be mediated by their influence on serotonin levels, using the quantitative transmission disequilibrium test (QTDT) and the restricted partition method (RPM), in a sample of 109 autistic children. We report a significant main effect of the HTR5A gene in autism (P = 0.0088), and a significant three-locus model comprising a synergistic interaction between the ITGB3 and SLC6A4 genes with an additive effect of HTR5A (P < 0.0010). In addition to the previously reported contribution of SLC6A4, we found significant associations of ITGB3 haplotypes with serotonin level distribution (P = 0.0163). The most significant models contributing to serotonin distribution were found for interactions between TPH1 rs4537731 and SLC6A4 haplotypes (P = 0.002) and between HTR1D rs6300 and SLC6A4 haplotypes (P = 0.013). In addition to the significant independent effects, evidence for interaction between SLC6A4 and ITGB3 markers was also found. The overall results implicate SLC6A4 and ITGB3 gene interactions in autism etiology and in serotonin level determination, providing evidence for a common underlying genetic mechanism and a molecular explanation for the association of platelet hyperserotonemia with autism.

Novel time-of-flight spectrometer for the analysis of positron annihilation induced Auger electrons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hugenschmidt, Christoph; Legl, Stefan; Physik-Department E21, Technische Universitaet Muenchen, James-Franck-Strasse, 85748 Garching

2006-10-15

Positron annihilation induced Auger-electron spectroscopy (PAES) has several advantages over conventional Auger-electron spectroscopy such as extremely high surface sensitivity and outstanding signal-to-noise ratio at the Auger-transition energy. In order to benefit from these prominent features a low-energy positron beam of high intensity is required for surface sensitive PAES studies. In addition, an electron energy analyzer is required, which efficiently detects the Auger electrons with acceptable energy resolution. For this reason a novel time-of-flight (TOF) spectrometer has been developed at the intense positron source NEPOMUC that allows PAES studies within short measurement time. This TOF-PAES setup combines a trochoidal filter andmore » a flight tube in a Faraday cage in order to achieve an improved energy resolution of about 1 eV at high electron energies up to E{approx_equal}1000 eV. The electron flight time is the time between the annihilation radiation at the sample and when the electron hits a microchannel plate detector at the end of the flight tube.« less

Novel time-of-flight spectrometer for the analysis of positron annihilation induced Auger electrons

NASA Astrophysics Data System (ADS)

Hugenschmidt, Christoph; Legl, Stefan

2006-10-01

Positron annihilation induced Auger-electron spectroscopy (PAES) has several advantages over conventional Auger-electron spectroscopy such as extremely high surface sensitivity and outstanding signal-to-noise ratio at the Auger-transition energy. In order to benefit from these prominent features a low-energy positron beam of high intensity is required for surface sensitive PAES studies. In addition, an electron energy analyzer is required, which efficiently detects the Auger electrons with acceptable energy resolution. For this reason a novel time-of-flight (TOF) spectrometer has been developed at the intense positron source NEPOMUC that allows PAES studies within short measurement time. This TOF-PAES setup combines a trochoidal filter and a flight tube in a Faraday cage in order to achieve an improved energy resolution of about 1eV at high electron energies up to E ≈1000eV. The electron flight time is the time between the annihilation radiation at the sample and when the electron hits a microchannel plate detector at the end of the flight tube.

Dark matter "transporting" mechanism explaining positron excesses

NASA Astrophysics Data System (ADS)

Kim, Doojin; Park, Jong-Chul; Shin, Seodong

2018-04-01

We propose a novel mechanism to explain the positron excesses, which are observed by satellite-based telescopes including PAMELA and AMS-02, in dark matter (DM) scenarios. The novelty behind the proposal is that it makes direct use of DM around the Galactic Center where DM populates most densely, allowing us to avoid tensions from cosmological and astrophysical measurements. The key ingredients of this mechanism include DM annihilation into unstable states with a very long laboratory-frame life time and their "retarded" decay near the Earth to electron-positron pair(s) possibly with other (in)visible particles. We argue that this sort of explanation is not in conflict with relevant constraints from big bang nucleosynthesis and cosmic microwave background. Regarding the resultant positron spectrum, we provide a generalized source term in the associated diffusion equation, which can be readily applicable to any type of two-"stage" DM scenarios wherein production of Standard Model particles occurs at completely different places from those of DM annihilation. We then conduct a data analysis with the recent AMS-02 data to validate our proposal.

Optical and positron annihilation spectroscopic studies on PMMA polymer doped by rhodamine B/chloranilic acid charge transfer complex: Special relevance to the effect of γ-ray irradiation

NASA Astrophysics Data System (ADS)

Hassan, H. E.; Refat, Moamen S.; Sharshar, T.

2016-04-01

Polymeric sheets of poly (methylmethaclyerate) (PMMA) containing charge transfer (CT) complex of rhodamine B/chloranilic acid (Rho B/CHA) were synthesized in methanol solvent at room temperature. The systematic analysis done on the Rho B and its CT complex in the form of powder or polymeric sheets confirmed their structure and thermal stability. The IR spectra interpreted the charge transfer mode of interaction between the CHA central positions and the terminal carboxylic group. The polymer sheets were irradiated with 70 kGy of γ radiation using 60Co source to study the enhanced changes in the structure and optical parameters. The microstructure changes of the PMMA sheets caused by γ-ray irradiation were analyzed using positron annihilation lifetime (PAL) and positron annihilation Doppler broadening (PADB) techniques. The positron life time components (τi) and their corresponding intensities (Ii) as well as PADB line-shape parameters (S and W) were found to be highly sensitive to the enhanced disorder occurred in the organic chains of the polymeric sheets due to γ-irradiation.

Positron induced scattering cross sections for hydrocarbons relevant to plasma

NASA Astrophysics Data System (ADS)

Singh, Suvam; Antony, Bobby

2018-05-01

This article explores positron scattering cross sections by simple hydrocarbons such as ethane, ethene, ethyne, propane, and propyne. Chemical erosion processes occurring on the surface due to plasma-wall interactions are an abundant source of hydrocarbon molecules which contaminate the hydrogenic plasma. These hydrocarbons play an important role in the edge plasma region of Tokamak and ITER. In addition to this, they are also one of the major components in the planetary atmospheres and astrophysical mediums. The present work focuses on calculation of different positron impact interactions with simple hydrocarbons in terms of the total cross section (Qtot), elastic cross section (Qel), direct ionization cross section (Qion), positronium formation cross section (Qps), and total ionization cross section (Qtion). Knowing that the positron-plasma study is one of the trending fields, the calculated data have diverse plasma and astrophysical modeling applications. A comprehensive study of Qtot has been provided where the inelastic cross sections have been reported for the first time. Comparisons are made with those available from the literature, and a good agreement is obtained with the measurements.

Cosmic ray electrons and positrons from supernova explosions of massive stars.

PubMed

Biermann, P L; Becker, J K; Meli, A; Rhode, W; Seo, E S; Stanev, T

2009-08-07

We attribute the recently discovered cosmic ray electron and cosmic ray positron excess components and their cutoffs to the acceleration in the supernova shock in the polar cap of exploding Wolf-Rayet and red supergiant stars. Considering a spherical surface at some radius around such a star, the magnetic field is radial in the polar cap as opposed to most of 4pi (the full solid angle), where the magnetic field is nearly tangential. This difference yields a flatter spectrum, and also an enhanced positron injection for the cosmic rays accelerated in the polar cap. This reasoning naturally explains the observations. Precise spectral measurements will be the test, as this predicts a simple E;{-2} spectrum for the new components in the source, steepened to E;{-3} in observations with an E;{-4} cutoff.

Hypothesis: SLC12A3 Polymorphism modifies thiazide hypersensitivity of antenatal Bartter syndrome to thiazide resistance.

PubMed

Mammen, Cherry; Rupps, Rosemarie; Trnka, Peter; Boerkoel, Cornelius F

2012-02-01

We report a 5-year-old boy with thiazide-resistant Bartter syndrome. This is highly unusual since thiazide hypersensitivity is a common diagnostic finding in Bartter syndrome patients. Subsequent molecular testing identified compound heterozygosity for two novel mutations in KCNJ1, (c.556A > G and c.683G > A) which is associated with Bartter syndrome, and a paternally inherited polymorphism in SLC12A3 (c.791G > C). Mutations in SLC12A3 cause the thiazide-resistant tubulopathy Gitelman syndrome. Based on published studies of this polymorphism in SLC12A3 and the features of the proband's father, we postulate that this polymorphism modifies the phenotype of Bartter syndrome in the proband to thiazide resistance. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

The pre-B cell receptor: turning autoreactivity into self-defense.

PubMed

Vettermann, Christian; Jäck, Hans-Martin

2010-05-01

The first step in establishing the antibody repertoire in humans and mice is the rearrangement of immunoglobulin heavy chain (HC) genes in early B lineage cells. These cells then assemble microHCs with surrogate light chains (SLC) into a pre-B cell receptor (pre-BCR). We propose that the pre-BCR has evolved from an ancient autoreactive BCR, since the SLC is an autoreactive entity that binds to the pre-BCR itself and to other self-antigens. Abrogation of autoreactivity in the SLC diminishes pre-BCR signaling and impairs the clonal expansion of pre-B cells producing functional microHCs. Since SLC expression is restricted to pre-B cells, the autoreactivity encoded by the pre-BCR can be utilized to pre-select the antibody repertoire, while simultaneously avoiding the formation of autoreactive B lymphocytes. Copyright 2010 Elsevier Ltd. All rights reserved.

An evaluation of gap-filled Landsat SLC-off imagery for wildland fire burn severity mapping

USGS Publications Warehouse

Howard, Stephen M.; Lacasse, James M.

2004-01-01

n May 31, 2003 unusual artifacts appeared within image data collected by the Enhanced Thematic Mapper plus (ETM+) instrument on-board the Landsat 7 spacecraft. The U.S. Geological Survey (USGS), with the support of NASA, has been working to find a means of compensating for the data gaps that result from a failure of the instrument’s scan line corrector (SLC). The SLC is an electromechanical device that compensates for the forward motion of the spacecraft by modifying the instrument’s optical path. The problem is likely due to a mechanical failure of the device for which there is no redundancy and that cannot be repaired or coaxed back into service. Further information regarding Landsat 7 and the SLC failure can be found at the Landsat Project home page (http://landsat7.usgs.gov).

SLC6A4 expression and anti-proliferative responses to serotonin transporter ligands chlomipramine and fluoxetine in primary B-cell malignancies.

PubMed

Chamba, Anita; Holder, Michelle J; Jarrett, Ruth F; Shield, Lesley; Toellner, Kai M; Drayson, Mark T; Barnes, Nicholas M; Gordon, John

2010-08-01

B-cell lines of diverse neoplastic origin express the serotonin transporter (SERT/SLC6A4) and growth arrest in response to SERT-ligands, including the antidepressants chlomipramine and fluoxetine. Here we detail SLC6A4 transcript (Q-PCR) and protein (FACS) expression in primary cells from patients with: chronic lymphocytic leukaemia; mantle cell lymphoma; follicular lymphoma; Burkitt's lymphoma; and diffuse large B-cell lymphoma. The ability of the SERT-binding antidepressants to impact the growth of these cells when sustained on CD154-transfected fibroblasts was also determined. The results reveal a broad spectrum of primary B-cell malignancies expressing SLC6A4 with a proportion additionally displaying growth arrest on SERT-ligand exposure. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

SLC2A9 and ZNF518B polymorphisms correlate with gout-related metabolic indices in Chinese Tibetan populations.

PubMed

Zhang, X Y; Geng, T T; Liu, L J; Yuan, D Y; Feng, T; Kang, L L; Jin, T B; Chen, C

2015-08-19

Current evidence suggests that heredity and metabolic syndrome contribute to gout progression. SLC2A9 and ZNF518B may play a role in gout progression in different populations, but no studies have focused on the Tibetan Chinese population. In this study, we determined whether variations in these 2 genes were correlated with gout-related indices in Chinese-Tibetan gout patients. We detected 6 single nucleotide polymorphisms in SLC2A9 and ZNF518B in 319 Chinese Tibetan gout patients. One-way analysis of variance was used to evaluate the polymorphisms' effects on gout based on mean serum levels of metabolism indicators. Polymorphisms in SLC2A9 and ZNF518B affected multiple risk factors related to gout development. Significant differences in serum triglyceride levels and high-density lipoprotein-cholesterol level were detected between different genotypic groups with SLC2A9 polymorphisms rs13129697 (P = 0.022), rs4447863 (P = 0.018), and rs1014290 (P = 0.045). Similarly in ZNF518B, rs3217 (P = 0.016) and rs10016022 (P = 0.046) were associated with high creatinine and glucose levels, respectively. This study is the first to investigate and identify positive correlations between SLC2A9 and ZNF518B gene polymorphisms and metabolic indices in Tibetan gout patients. We found significant evidence indicating that genetic polymorphisms affect gout-related factors in Chinese Tibetan populations.

Slc15a1 is involved in the transport of synthetic F5-peptide into the seminiferous epithelium in adult rat testes

PubMed Central

Su, Linlin; Zhang, Yufei; Cheng, Yan C.; Lee, Will M.; Ye, Keping; Hu, Dahai

2015-01-01

Spermiation and BTB restructuring, two critical cellular events that occur across seminiferous epithelium in mammalian testis during spermatogenesis, are tightly coordinated by biologically active peptides released from laminin chains. Our earlier study reported that F5-peptide, synthesized based on a stretch of 50 amino acids within laminin-γ3 domain IV, could reversibly induce the impairment of spermatogenesis, disruption of BTB integrity, and germ cell loss, and thus is a promising male contraceptive. However, how F5-peptide when administered intratesticularly enters seminiferous tubules and exerts effects beyond BTB is currently unknown. Here we demonstrated that Slc15a1, a peptide transporter also known as Pept1, was predominantly present in peritubular myoid cells, interstitial Leydig cells, vascular endothelial cells and germ cells, while absent in Sertoli cells or BTB site. The steady-state protein level of Slc15a1 in adult rat testis was not affected by F5-peptide treatment. Knockdown of Slc15a1 by in vivo RNAi in rat testis was shown to prevent F5-peptide induced disruptive effects on spermatogenesis. This study suggests that Slc15a1 is involved in the transport of synthetic F5-peptide into seminiferous epithelium, and thus Slc15a1 is a novel target in testis that could be genetically modified to improve the bioavailability of F5-peptide as a prospective male contraceptive. PMID:26537751

Slc15a1 is involved in the transport of synthetic F5-peptide into the seminiferous epithelium in adult rat testes.

PubMed

Su, Linlin; Zhang, Yufei; Cheng, Yan C; Lee, Will M; Ye, Keping; Hu, Dahai

2015-11-05

Spermiation and BTB restructuring, two critical cellular events that occur across seminiferous epithelium in mammalian testis during spermatogenesis, are tightly coordinated by biologically active peptides released from laminin chains. Our earlier study reported that F5-peptide, synthesized based on a stretch of 50 amino acids within laminin-γ3 domain IV, could reversibly induce the impairment of spermatogenesis, disruption of BTB integrity, and germ cell loss, and thus is a promising male contraceptive. However, how F5-peptide when administered intratesticularly enters seminiferous tubules and exerts effects beyond BTB is currently unknown. Here we demonstrated that Slc15a1, a peptide transporter also known as Pept1, was predominantly present in peritubular myoid cells, interstitial Leydig cells, vascular endothelial cells and germ cells, while absent in Sertoli cells or BTB site. The steady-state protein level of Slc15a1 in adult rat testis was not affected by F5-peptide treatment. Knockdown of Slc15a1 by in vivo RNAi in rat testis was shown to prevent F5-peptide induced disruptive effects on spermatogenesis. This study suggests that Slc15a1 is involved in the transport of synthetic F5-peptide into seminiferous epithelium, and thus Slc15a1 is a novel target in testis that could be genetically modified to improve the bioavailability of F5-peptide as a prospective male contraceptive.

Homozygous SLC6A17 Mutations Cause Autosomal-Recessive Intellectual Disability with Progressive Tremor, Speech Impairment, and Behavioral Problems

PubMed Central

Iqbal, Zafar; Willemsen, Marjolein H.; Papon, Marie-Amélie; Musante, Luciana; Benevento, Marco; Hu, Hao; Venselaar, Hanka; Wissink-Lindhout, Willemijn M.; Vulto-van Silfhout, Anneke T.; Vissers, Lisenka E.L.M.; de Brouwer, Arjan P.M.; Marouillat, Sylviane; Wienker, Thomas F.; Ropers, Hans Hilger; Kahrizi, Kimia; Nadif Kasri, Nael; Najmabadi, Hossein; Laumonnier, Frédéric; Kleefstra, Tjitske; van Bokhoven, Hans

2015-01-01

We report on Dutch and Iranian families with affected individuals who present with moderate to severe intellectual disability and additional phenotypes including progressive tremor, speech impairment, and behavioral problems in certain individuals. A combination of exome sequencing and homozygosity mapping revealed homozygous mutations c.484G>A (p.Gly162Arg) and c.1898C>G (p.Pro633Arg) in SLC6A17. SLC6A17 is predominantly expressed in the brain, encodes a synaptic vesicular transporter of neutral amino acids and glutamate, and plays an important role in the regulation of glutamatergic synapses. Prediction programs and 3D modeling suggest that the identified mutations are deleterious to protein function. To directly test the functional consequences, we investigated the neuronal subcellular localization of overexpressed wild-type and mutant variants in mouse primary hippocampal neuronal cells. Wild-type protein was present in soma, axons, dendrites, and dendritic spines. p.Pro633Arg altered SLC6A17 was found in soma and proximal dendrites but did not reach spines. p.Gly162Arg altered SLC6A17 showed a normal subcellular distribution but was associated with an abnormal neuronal morphology mainly characterized by the loss of dendritic spines. In summary, our genetic findings implicate homozygous SLC6A17 mutations in autosomal-recessive intellectual disability, and their pathogenic role is strengthened by genetic evidence and in silico and in vitro functional analyses. PMID:25704603

Identification of SLC20A1 and SLC15A4 among other genes as potential risk factors for combined pituitary hormone deficiency.

PubMed

Simm, Franziska; Griesbeck, Anne; Choukair, Daniela; Weiß, Birgit; Paramasivam, Nagarajan; Klammt, Jürgen; Schlesner, Matthias; Wiemann, Stefan; Martinez, Cristina; Hoffmann, Georg F; Pfäffle, Roland W; Bettendorf, Markus; Rappold, Gudrun A

2017-10-26

PurposeCombined pituitary hormone deficiency (CPHD) is characterized by a malformed or underdeveloped pituitary gland resulting in an impaired pituitary hormone secretion. Several transcription factors have been described in its etiology, but defects in known genes account for only a small proportion of cases.MethodsTo identify novel genetic causes for congenital hypopituitarism, we performed exome-sequencing studies on 10 patients with CPHD and their unaffected parents. Two candidate genes were sequenced in further 200 patients. Genotype data of known hypopituitary genes are reviewed.ResultsWe discovered 51 likely damaging variants in 38 genes; 12 of the 51 variants represent de novo events (24%); 11 of the 38 genes (29%) were present in the E12.5/E14.5 pituitary transcriptome. Targeted sequencing of two candidate genes, SLC20A1 and SLC15A4, of the solute carrier membrane transport protein family in 200 additional patients demonstrated two further variants predicted as damaging. We also found combinations of de novo (SLC20A1/SLC15A4) and transmitted variants (GLI2/LHX3) in the same individuals, leading to the full-blown CPHD phenotype.ConclusionThese data expand the pituitary target genes repertoire for diagnostics and further functional studies. Exome sequencing has identified a combination of rare variants in different genes that might explain incomplete penetrance in CPHD.Genetics in Medicine advance online publication, 26 October 2017; doi:10.1038/gim.2017.165.

The SLC3 and SLC7 families of amino acid transporters.

PubMed

Fotiadis, Dimitrios; Kanai, Yoshikatsu; Palacín, Manuel

2013-01-01

Amino acids are necessary for all living cells and organisms. Specialized transporters mediate the transfer of amino acids across plasma membranes. Malfunction of these proteins can affect whole-body homoeostasis giving raise to diverse human diseases. Here, we review the main features of the SLC3 and SLC7 families of amino acid transporters. The SLC7 family is divided into two subfamilies, the cationic amino acid transporters (CATs), and the L-type amino acid transporters (LATs). The latter are the light or catalytic subunits of the heteromeric amino acid transporters (HATs), which are associated by a disulfide bridge with the heavy subunits 4F2hc or rBAT. These two subunits are glycoproteins and form the SLC3 family. Most CAT subfamily members were functionally characterized and shown to function as facilitated diffusers mediating the entry and efflux of cationic amino acids. In certain cells, CATs play an important role in the delivery of L-arginine for the synthesis of nitric oxide. HATs are mostly exchangers with a broad spectrum of substrates and are crucial in renal and intestinal re-absorption and cell redox balance. Furthermore, the role of the HAT 4F2hc/LAT1 in tumor growth and the application of LAT1 inhibitors and PET tracers for reduction of tumor progression and imaging of tumors are discussed. Finally, we describe the link between specific mutations in HATs and the primary inherited aminoacidurias, cystinuria and lysinuric protein intolerance. Copyright © 2012 Elsevier Ltd. All rights reserved.

Syndrome of Hepatic Cirrhosis, Dystonia, Polycythemia, and Hypermanganesemia Caused by Mutations in SLC30A10, a Manganese Transporter in Man

PubMed Central

Tuschl, Karin; Clayton, Peter T.; Gospe, Sidney M.; Gulab, Shamshad; Ibrahim, Shahnaz; Singhi, Pratibha; Aulakh, Roosy; Ribeiro, Reinaldo T.; Barsottini, Orlando G.; Zaki, Maha S.; Del Rosario, Maria Luz; Dyack, Sarah; Price, Victoria; Rideout, Andrea; Gordon, Kevin; Wevers, Ron A.; “Kling” Chong, W.K.; Mills, Philippa B.

2012-01-01

Environmental manganese (Mn) toxicity causes an extrapyramidal, parkinsonian-type movement disorder with characteristic magnetic resonance images of Mn accumulation in the basal ganglia. We have recently reported a suspected autosomal recessively inherited syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia in cases without environmental Mn exposure. Whole-genome mapping of two consanguineous families identified SLC30A10 as the affected gene in this inherited type of hypermanganesemia. This gene was subsequently sequenced in eight families, and homozygous sequence changes were identified in all affected individuals. The function of the wild-type protein and the effect of sequence changes were studied in the manganese-sensitive yeast strain Δpmr1. Expressing human wild-type SLC30A10 in the Δpmr1 yeast strain rescued growth in high Mn conditions, confirming its role in Mn transport. The presence of missense (c.266T>C [p.Leu89Pro]) and nonsense (c.585del [p.Thr196Profs∗17]) mutations in SLC30A10 failed to restore Mn resistance. Previously, SLC30A10 had been presumed to be a zinc transporter. However, this work has confirmed that SLC30A10 functions as a Mn transporter in humans that, when defective, causes Mn accumulation in liver and brain. This is an important step toward understanding Mn transport and its role in neurodegenerative processes. PMID:22341972

Serotonin Transporter Gene (SLC6A4) Polymorphism and Mucosal Serotonin Levels in Southeastern Iranian Patients with Irritable Bowel Syndrome

PubMed Central

Mohammadi, Mojgan; Tahmasebi Abdar, Hossein; Mollaei, Hamid Reza; Hajghani, Hossein; Baneshi, Mohammad Reza; Hayatbakhsh, Mohammad Mahdi

2017-01-01

BACKGROUND Irritable bowel syndrome (IBS) is a digestive system disorder with an unknown etiology. Serotonin has a key role in the secretion and motility of the intestine. Polymorphism in serotonin re-uptake transporter (SERT or SLC6A4) gene may have a functional role in the gut of patients with IBS. The aims of the present study were to investigate the association between SLC6A4 gene polymorphism and IBS and to detect the correlation between rectal serotonin levels and IBS sub-types. METHODS SLC6A4 gene polymorphism in 131 patients with IBS and 211 healthy controls were analysed using the quantitative polymerase chain reaction high-resolution melting (qPCR-HRM) curve technique. Serotonin was measured in rectal biopsies of patients with IBS using the enzyme-linked immunosorbent assay (ELISA) method. RESULTS The patients were categorized into three groups: IBS with diarrhoea (IBS-D): 70 patients, IBS with constipation (IBS-C): 18 patients, and IBS with mixed symptoms (IBS-M): 43 patients. The frequency of SLC6A4 s/s and l/s genotypes was significantly higher in IBS-C than IBS-D, IBS-M, and controls (p=0.036). Serotonin levels were similar in IBS sub-types. CONCLUSION SLC6A4 polymorphism is a possible candidate gene associated with the pathogenesis of IBS-C. Although serotonin levels did not differ in rectal biopsies of IBS sub-types, further investigation is recommended. PMID:28316763

Diagnostic Value of SLC26A4 Mutation Status in Hereditary Hearing Loss With EVA: A PRISMA-Compliant Meta-Analysis.

PubMed

Lu, Ya-Jie; Yao, Jun; Wei, Qin-Jun; Xing, Guang-Qian; Cao, Xin

2015-12-01

Many SLC26A4 mutations have been identified in patients with nonsyndromic enlarged vestibular aqueduct (EVA). However, the roles of SLC26A4 genotypes and phenotypes in hereditary deafness remain unexplained. This study aims to perform a meta-analysis based on the PRISMA statement to evaluate the diagnostic value of SLC26A4 mutant alleles and their correlations with multiethnic hearing phenotypes in EVA patients. The systematic literature search of the PubMed, Wiley Online Library, EMBASE, Web of Science, and Science Direct databases was conducted in English for articles published before July 15, 2015. Two investigators independently reviewed retrieved literature and evaluated eligibility. Discrepancy was resolved by discussion and a third investigator. Quality of included studies was evaluated using Newcastle-Ottawa Quality Assessment Scale. Data were synthesized using random-effect or fixed-effect models. The effect sizes were estimated by measuring odds ratios (ORs) with 95% confidence interval (CI). Twenty-five eligible studies involved 2294 cases with EVA data. A total of 272 SLC26A4 variations were found in deafness with EVA and 26 mutations of SCL26A4 had higher frequency. The overall OR was 646.71 (95% CI: 383.30-1091.15, P = 0.000). A total of 22 mutants were considered statistically significant in all ethnicities (ORs >1, P < 0.05). In particular, 8 mutants were specificity of EVA phenotypes in mutations of SLC26A4 for Asia deafness populations (ORs >1, P < 0.05), 4 mutants for Europe and North America (ORs >1, P < 0.05), and the IVS7-2A>G mutations in SLC26A4 were found to have the highest frequency in deafness individuals with EVA phenotype (62.42%). Moreover, subgroups for studies limited to cases with EVA phenotype, 11 mutants relevant risks (RRs) were P < 0.05, especially for IVS7-2A>G bi-allelic mutants assayed in a deafness population (RR = 0.880, P = 0.000). Diagnostic accuracy of SLC26A4 mutation results also identified the significant association of IVS7-2A>G (AUC = 0.99, 95% CI: 0.97-0.99) and p.H723R (AUC = 0.99, 95% CI: 0.98-1.00) detecting deafness with EVA. To conclude, the IVS7-2A>G and H723R in SLC26A4 present a significant predicting value and discriminatory ability for clinical use on diagnosis of EVA within a deafness population.

Particle Acceleration and Magnetic Field Generation in Electron-Positron Relativistic Shocks

NASA Technical Reports Server (NTRS)

Nishikawa, K.-I.; Hardee, P.; Richardson, G.; Preece, R.; Sol, H.; Fishman, G. J.

2004-01-01

Shock acceleration is an ubiquitous phenomenon in astrophysical plasmas. Plasma waves and their associated instabilities (e.g., Buneman, Weibel and other two-stream instabilities) created in collisionless shocks are responsible for particle (electron, positron, and ion) acceleration. Using a 3-D relativistic electromagnetic particle (REMP) code, we have investigated particle acceleration associated with a relativistic electron-positron jet front propagating into an ambient electron-positron plasma with and without initial magnetic fields. We find small differences in the results for no ambient and modest ambient magnetic fields. Simulations show that the Weibel instability created in the collisionless shock front accelerates jet and ambient particles both perpendicular and parallel to the jet propagation direction. The non-linear fluctuation amplitudes of densities, currents, electric, and magnetic fields in the electron-positron shock are larger than those found in the electron-ion shock studied in a previous paper. This comes from the fact that both electrons and positrons contribute to generation of the Weibel instability. Additionally, we have performed simulations with different electron skin depths. We find that growth times scale inversely with the plasma frequency, and the sizes of structures created by the Weibel instability scale proportional to the electron skin depth. This is the expected result and indicates that the simulations have sufficient grid resolution. While some Fermi acceleration may occur at the jet front, the majority of electron and positron acceleration takes place behind the jet front and cannot be characterized as Fermi acceleration. The simulation results show that the Weibel instability is responsible for generating and amplifying nonuniform, small-scale magnetic fields which contribute to the electron's (positron's) transverse deflection behind the jet head. This small scale magnetic field structure is appropriate to the generation of "jitter" radiation from deflected electrons (positrons) as opposed to synchrotron radiation. The jitter radiation has different properties than synchrotron radiation calculated assuming a a uniform magnetic field. The jitter radiation resulting from small scale magnetic field structures may be important for understanding the complex time structure and spectral evolution observed in gamma-ray bursts or other astrophysical sources containing relativistic jets and relativistic collisionless shocks.

Particle Acceleration and Magnetic Field Generation in Electron-Positron Relativistic Shocks

NASA Technical Reports Server (NTRS)

Nishikawa, K.-L.; Hardee, P.; Richardson, G.; Preece, R.; Sol, H.; Fishman, G. J.

2004-01-01

Shock acceleration is an ubiquitous phenomenon in astrophysical plasmas. Plasma waves and their associated instabilities (e.g., Buneman, Weibel and other two-stream instabilities) created in collisionless shocks are responsible for particle (electron, positron, and ion) acceleration. Using a 3-D relativistic electromagnetic particle (REMP) code, we have investigated particle acceleration associated with a relativistic electron-positron jet front propagating into an ambient electron-positron plasma with and without initial magnetic fields. We find small differences in the results for no ambient and modest ambient magnetic fields. Simulations show that the Weibel instability created in the collisionless shock front accelerates jet and ambient particles both perpendicular and parallel to the jet propagation direction. The non-linear fluctuation amplitudes of densities, currents, electric, and magnetic fields in the electron-positron shock are larger than those found in the electron-ion shock studied in a previous paper at the comparable simulation time. This comes from the fact that both electrons and positrons contribute to generation of the Weibel instability. Additionally, we have performed simulations with different electron skin depths. We find that growth times scale inversely with the plasma frequency, and the sizes of structures created by the Weibel instability scale proportional to the electron skin depth. This is the expected result and indicates that the simulations have sufficient grid resolution. While some Fermi acceleration may occur at the jet front, the majority of electron and positron acceleration takes place behind the jet front and cannot be characterized as Fermi acceleration. The simulation results show that the Weibel instability is responsible for generating and amplifying nonuniform: small-scale magnetic fields which contribute to the electron's (positron's) transverse deflection behind the jet head. This small scale magnetic field structure is appropriate to the generation of jitter radiation from deflected electrons (positrons) as opposed to synchrotron radiation. The jitter radiation has different properties than synchrotron radiation calculated assuming a a uniform magnetic field. The jitter radiation resulting from small scale magnetic field structures may be important for understanding the complex time structure and spectral evolution observed in gamma-ray bursts or other astrophysical sources containing relativistic jets and relativistic collisionless shocks.

Particle Acceleration and Magnetic Field Generation in Electron-Positron Relativistic Shocks

NASA Technical Reports Server (NTRS)

Nishikawa, K.-I.; Hardee, P.; Richardson, G.; Preece, R.; Sol, H.; Fishman, G. J.

2005-01-01

Shock acceleration is a ubiquitous phenomenon in astrophysical plasmas. Plasma waves and their associated instabilities (e.g., Buneman, Weibel, and other two-stream instabilities) created in collisionless shocks are responsible for particle (electron, positron, and ion) acceleration. Using a three-dimensional relativistic electromagnetic particle (REMP) code, we have investigated particle acceleration associated with a relativistic electron-positron jet front propagating into an ambient electron-positron plasma with and without initial magnetic fields. We find small differences in the results for no ambient and modest ambient magnetic fields. New simulations show that the Weibel instability created in the collisionless shock front accelerates jet and ambient particles both perpendicular and parallel to the jet propagation direction. Furthermore, the nonlinear fluctuation amplitudes of densities, currents, and electric and magnetic fields in the electron-positron shock are larger than those found in the electron-ion shock studied in a previous paper at a comparable simulation time. This comes from the fact that both electrons and positrons contribute to generation of the Weibel instability. In addition, we have performed simulations with different electron skin depths. We find that growth times scale inversely with the plasma frequency, and the sizes of structures created by tine Weibel instability scale proportionally to the electron skin depth. This is the expected result and indicates that the simulations have sufficient grid resolution. While some Fermi acceleration may occur at the jet front, the majority of electron and positron acceleration takes place behind the jet front and cannot be characterized as Fermi acceleration. The simulation results show that the Weibel instability is responsible for generating and amplifying nonuniform, small-scale magnetic fields, which contribute to the electron s (positron s) transverse deflection behind the jet head. This small- scale magnetic field structure is appropriate to the generation of "jitter" radiation from deflected electrons (positrons) as opposed to synchrotron radiation. The jitter radiation has different properties than synchrotron radiation calculated assuming a uniform magnetic field. The jitter radiation resulting from small-scale magnetic field structures may be important for understanding the complex time structure and spectral evolution observed in gamma-ray bursts or other astrophysical sources containing relativistic jets and relativistic collisionless shocks.

Isoflavone genistein inhibits estrogen-induced chloride and bicarbonate secretory mechanisms in the uterus in rats.

PubMed

Chinigarzadeh, Asma; Karim, Kamarulzaman; Muniandy, Sekaran; Salleh, Naguib

2017-04-01

We hypothesized that genistein could affect the chloride (Cl - ) and bicarbonate (HCO 3 - ) secretory mechanisms in uterus. Ovariectomized female rats were given estradiol or estradiol plus progesterone with 25, 50, or 100 mg/kg/day genistein. Following completion of the treatment, uterine fluid Cl - and HCO 3 - concentrations were determined by in vivo uterine perfusion. Uteri were subjected for molecular biological analysis (Western blot, qPCR, and immunohistochemistry) to detect levels of expression of Cystic Fibrosis transmembrane regulator (CFTR), Cl - /HCO 3 - exchanger (SLC26a6), Na + /HCO 3 - cotransporter (SLC4a4), and estrogen receptor (ER)-α and β. Coadministration of genistein resulted in decrease in Cl - and HCO 3 - concentrations and expression of CFTR, SLC26a6, SLC4a4, and ER-α and ER-β in the uteri of estradiol-treated rats. In estradiol plus progesterone-treated rats, a significant increase in the above parameters were observed following high-dose genistein treatment except for the SLC24a4 level. In conclusion, genistein-induced changes in the uterus could affect the reproductive processes that might result in infertility. © 2016 Wiley Periodicals, Inc.

L-Theanine Administration Modulates the Absorption of Dietary Nutrients and Expression of Transporters and Receptors in the Intestinal Mucosa of Rats.

PubMed

Yan, Qiongxian; Tong, Haiou; Tang, Shaoxun; Tan, Zhiliang; Han, Xuefeng; Zhou, Chuanshe

2017-01-01

L-theanine has various advantageous functions for human health; whether or not it could mediate the nutrients absorption is unknown yet. The effects of L-theanine on intestinal nutrients absorption were investigated using rats ingesting L-theanine solution (0, 50, 200, and 400 mg/kg body weight) per day for two weeks. The decline of insulin secretion and glucose concentration in the serum was observed by L-theanine. Urea and high-density lipoprotein were also reduced by 50 mg/kg L-theanine. Jejunal and ileac basic amino acids transporters SLC7a1 and SLC7a9 , neutral SLC1a5 and SLC16a10 , and acidic SLC1a1 expression were upregulated. The expression of intestinal SGLT3 and GLUT5 responsible for carbohydrates uptake and GPR120 and FABP2 associated with fatty acids transport were inhibited. These results indicated that L-theanine could inhibit the glucose uptake by downregulating the related gene expression in the small intestine of rats. Intestinal gene expression of transporters responding to amino acids absorption was stimulated by L-theanine administration.

Beam position monitoring system at CESR

NASA Astrophysics Data System (ADS)

Billing, M. G.; Bergan, W. F.; Forster, M. J.; Meller, R. E.; Rendina, M. C.; Rider, N. T.; Sagan, D. C.; Shanks, J.; Sikora, J. P.; Stedinger, M. G.; Strohman, C. R.; Palmer, M. A.; Holtzapple, R. L.

2017-09-01

The Cornell Electron-positron Storage Ring (CESR) has been converted from a High Energy Physics electron-positron collider to operate as a dedicated synchrotron light source for the Cornell High Energy Synchrotron Source (CHESS) and to conduct accelerator physics research as a test accelerator, capable of studying topics relevant to future damping rings, colliders and light sources. Some of the specific topics that were targeted for the initial phase of operation of the storage ring in this mode, labeled CESRTA (CESR as a Test Accelerator), included 1) tuning techniques to produce low emittance beams, 2) the study of electron cloud development in a storage ring and 3) intra-beam scattering effects. The complete conversion of CESR to CESRTA occurred over a several year period and is described elsewhere. As a part of this conversion the CESR beam position monitoring (CBPM) system was completely upgraded to provide the needed instrumental capabilities for these studies. This paper describes the new CBPM system hardware, its function and representative measurements performed by the upgraded system.

Detection efficiency calculation for photons, electrons and positrons in a well detector. Part I: Analytical model

NASA Astrophysics Data System (ADS)

Pommé, S.

2009-06-01

An analytical model is presented to calculate the total detection efficiency of a well-type radiation detector for photons, electrons and positrons emitted from a radioactive source at an arbitrary position inside the well. The model is well suited to treat a typical set-up with a point source or cylindrical source and vial inside a NaI well detector, with or without lead shield surrounding it. It allows for fast absolute or relative total efficiency calibrations for a wide variety of geometrical configurations and also provides accurate input for the calculation of coincidence summing effects. Depending on its accuracy, it may even be applied in 4π-γ counting, a primary standardisation method for activity. Besides an accurate account of photon interactions, precautions are taken to simulate the special case of 511 keV annihilation quanta and to include realistic approximations for the range of (conversion) electrons and β -- and β +-particles.

New central drift chamber for the MARK II at SLC

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bartelt, J.E.

A new central drift chamber has been constructed for the Mark II detector for use at the new SLAC Linear Collider (SLC). The design of the chamber is based on a multi-sense-wire cell of the jet chamber type. In addition to drift-time measurements, pulse-height measurements from the sense wires provide electron-hadron separation by dE/dx. The chamber has been tested in operation at PEP before its move to the SLC. The design and construction are described, and measurements from the new chamber are presented.

Harvesting the decay energy of 26Al to drive lightning discharge in protoplanetary discs

NASA Astrophysics Data System (ADS)

Johansen, Anders; Okuzumi, Satoshi

2018-01-01

Chondrules in primitive meteorites likely formed by recrystallisation of dust aggregates that were flash-heated to nearly complete melting. Chondrules may represent the building blocks of rocky planetesimals and protoplanets in the inner regions of protoplanetary discs, but the source of ubiquitous thermal processing of their dust aggregate precursors remains elusive. Here we demonstrate that escape of positrons released in the decay of the short-lived radionuclide 26Al leads to a large-scale charging of dense pebble structures, resulting in neutralisation by lightning discharge and flash-heating of dust and pebbles. This charging mechanism is similar to a nuclear battery where a radioactive source charges a capacitor. We show that the nuclear battery effect operates in circumplanetesimal pebble discs. The extremely high pebble densities in such discs are consistent with conditions during chondrule heating inferred from the high abundance of sodium within chondrules. The sedimented mid-plane layer of the protoplanetary disc may also be prone to charging by the emission of positrons, if the mass density of small dust there is at least an order of magnitude above the gas density. Our results imply that the decay energy of 26Al can be harvested to drive intense lightning activity in protoplanetary discs. The total energy stored in positron emission is comparable to the energy needed to melt all solids in the protoplanetary disc. The efficiency of transferring the positron energy to the electric field nevertheless depends on the relatively unknown distribution and scale-dependence of pebble density gradients in circumplanetesimal pebble discs and in the protoplanetary disc mid-plane layer.

SLC injector modeling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hanerfeld, H; Herrmannsfeldt, W.B.; James, M.B.

1985-03-01

The injector for the Stanford Linear Collider is being studied using the fully electromagnetic particle-in-cell program MASK. The program takes account of cylindrically symmetrical rf fields from the external source, as well as fields produced by the beam and dc magnetic fields. It calculates the radial and longitudinal motion of electrons and plots their positions in various planes in phase space. Bunching parameters can be optimized and insights into the bunching process and emittance growth have been gained. The results of the simulations are compared to the experimental results.

DiffSLC: A graph centrality method to detect essential proteins of a protein-protein interaction network.

PubMed

Mistry, Divya; Wise, Roger P; Dickerson, Julie A

2017-01-01

Identification of central genes and proteins in biomolecular networks provides credible candidates for pathway analysis, functional analysis, and essentiality prediction. The DiffSLC centrality measure predicts central and essential genes and proteins using a protein-protein interaction network. Network centrality measures prioritize nodes and edges based on their importance to the network topology. These measures helped identify critical genes and proteins in biomolecular networks. The proposed centrality measure, DiffSLC, combines the number of interactions of a protein and the gene coexpression values of genes from which those proteins were translated, as a weighting factor to bias the identification of essential proteins in a protein interaction network. Potentially essential proteins with low node degree are promoted through eigenvector centrality. Thus, the gene coexpression values are used in conjunction with the eigenvector of the network's adjacency matrix and edge clustering coefficient to improve essentiality prediction. The outcome of this prediction is shown using three variations: (1) inclusion or exclusion of gene co-expression data, (2) impact of different coexpression measures, and (3) impact of different gene expression data sets. For a total of seven networks, DiffSLC is compared to other centrality measures using Saccharomyces cerevisiae protein interaction networks and gene expression data. Comparisons are also performed for the top ranked proteins against the known essential genes from the Saccharomyces Gene Deletion Project, which show that DiffSLC detects more essential proteins and has a higher area under the ROC curve than other compared methods. This makes DiffSLC a stronger alternative to other centrality methods for detecting essential genes using a protein-protein interaction network that obeys centrality-lethality principle. DiffSLC is implemented using the igraph package in R, and networkx package in Python. The python package can be obtained from git.io/diffslcpy. The R implementation and code to reproduce the analysis is available via git.io/diffslc.

An update on the genetic architecture of hyperuricemia and gout.

PubMed

Merriman, Tony R

2015-04-10

Genome-wide association studies that scan the genome for common genetic variants associated with phenotype have greatly advanced medical knowledge. Hyperuricemia is no exception, with 28 loci identified. However, genetic control of pathways determining gout in the presence of hyperuricemia is still poorly understood. Two important pathways determining hyperuricemia have been confirmed (renal and gut excretion of uric acid with glycolysis now firmly implicated). Major urate loci are SLC2A9 and ABCG2. Recent studies show that SLC2A9 is involved in renal and gut excretion of uric acid and is implicated in antioxidant defense. Although etiological variants at SLC2A9 are yet to be identified, it is clear that considerable genetic complexity exists at the SLC2A9 locus, with multiple statistically independent genetic variants and local epistatic interactions. The positions of implicated genetic variants within or near chromatin regions involved in transcriptional control suggest that this mechanism (rather than structural changes in SLC2A9) is important in regulating the activity of SLC2A9. ABCG2 is involved primarily in extra-renal uric acid under-excretion with the etiological variant influencing expression. At the other 26 loci, probable causal genes can be identified at three (PDZK1, SLC22A11, and INHBB) with strong candidates at a further 10 loci. Confirmation of the causal gene will require a combination of re-sequencing, trans-ancestral mapping, and correlation of genetic association data with expression data. As expected, the urate loci associate with gout, although inconsistent effect sizes for gout require investigation. Finally, there has been no genome-wide association study using clinically ascertained cases to investigate the causes of gout in the presence of hyperuricemia. In such a study, use of asymptomatic hyperurcemic controls would be expected to increase the ability to detect genetic associations with gout.

Regulation of Facilitative Glucose Transporters and AKT/MAPK/PRKAA Signaling via Estradiol and Progesterone in the Mouse Uterine Epithelium1

PubMed Central

Kim, Sung Tae; Moley, Kelle H.

2009-01-01

Adequate uterine glucose metabolism is an essential part of embryo implantation and the development of an adequate utero-fetal environment. However, expression of facilitative glucose transporters (GLUTs [solute transporter family SLC2A]) and AKT/MAPK/PRKAA (PRKAA) signaling has not been described in the mouse uterine cells, to our knowledge. The objective of this study was to determine the hormonal regulation of SLC2A protein expression and AKT/MAPK/PRKAA signaling in the mouse uterine epithelial cells during estrous cycles and peri-implantation periods. SLC2As 1, 4, 8, and 9B were highly expressed in the luminal and glandular epithelia of estrous stage. In metestrous and diestrous stages, expression of SLC2As 1, 4, 8, and 9B was lower than that in proestrous stage. Levels of activated phospho-AKT (p-AKT), p-MAPK3, and p-MAPK1 also varied during the estrous cycle. Estrogen and progesterone injection in an ovariectomized mouse (delayed implantation model) resulted in a decrease and an increase, respectively, in expression of GLUTs in the luminal epithelial cells of the uterus. The expression of SLC2A1, SLC2A8, SLC2A9B, p-AKT, p-MAPK3/1, and p-PRKAA was increased in the decidual region of the implantation sites and was significantly increased in the uterus of activated implantation. Using an artificial decidualization mouse model, it was also demonstrated that expression of the same GLUTs, p-MAPK3/1, and p-PRKAA was dramatically higher in the decidualized uteri than that in the control uteri. These results suggest that steroid hormones regulate expression of uterine epithelial GLUTs possibly through AKT/MAPK/PRKAA signaling pathways and that glucose utilization may have an important role in decidualization and possibly in the maintenance of pregnancy. PMID:19208550

Deletions at SLC18A1 increased the risk of CRC and lower SLC18A1 expression associated with poor CRC outcome.

PubMed

Zhang, Dandan; Li, Zhenli; Xu, Xiaohong; Zhou, Dan; Tang, Shunli; Yin, Xiaoyang; Xu, Fangying; Li, Hui; Zhou, Yuan; Zhu, Tao; Deng, Hong; Zhang, Shuai; Huang, Qiong; Wang, Jing; Yin, Wei; Zhu, Yimin; Lai, Maode

2017-10-26

Copy number variations (CNVs) contribute to the development of colorectal cancer (CRC). We conducted a two-stage association study to identify CNV risk loci for CRC. We performed a gene-based rare CNV study on 694 sporadic CRC and 1641 controls using Illumina Human-OmniExpress-12v1.0 BeadChips, and further replicated in 934 CRC cases and 2680 controls for risk CNVs by using TaqMan Copy Number Assay. Tumor buddings, cancer cells in the center of primary tumor and normal intestinal epithelial cells were captured using laser capture microdissection (LCM) and were assayed using AffymetrixGeneChip® Human Genome U133 Plus 2.0 Array. In addition, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus data were assessed for the effects of risk CNVs. We found that germline deletions affecting the last six exons of SLC18A1 significantly associated with CRC with a combined P value of 6.4 × 10-5 by a two-stage analysis. Both in TCGA CRC RNA seq dataset and GDS4382, SLC18A1 was significantly down regulated in CRC tissues than in paired normal tissues (N = 32 and 17 pairs, P = 0.004 and 0.009, respectively). In LCM samples, similar observations were obtained that the expression levels of SLC18A1 in the tumor buddings, cancer cells in the center of primary tumor, and stroma of both tumor budding and cancer cells were lower than normal intestinal epithelial and stromal cells (fold change = 0.17-0.62, 0.12-0.57 and 0.37-0.68, respectively). In summary, the germline deletions at SLC18A1 contributed to the development of CRC. The role of SLC18A1 required further exploration. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

SLC2A3 single-nucleotide polymorphism and duplication influence cognitive processing and population-specific risk for attention-deficit/hyperactivity disorder.

PubMed

Merker, Sören; Reif, Andreas; Ziegler, Georg C; Weber, Heike; Mayer, Ute; Ehlis, Ann-Christine; Conzelmann, Annette; Johansson, Stefan; Müller-Reible, Clemens; Nanda, Indrajit; Haaf, Thomas; Ullmann, Reinhard; Romanos, Marcel; Fallgatter, Andreas J; Pauli, Paul; Strekalova, Tatyana; Jansch, Charline; Vasquez, Alejandro Arias; Haavik, Jan; Ribasés, Marta; Ramos-Quiroga, Josep Antoni; Buitelaar, Jan K; Franke, Barbara; Lesch, Klaus-Peter

2017-07-01

Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder with profound cognitive, behavioral, and psychosocial impairments with persistence across the life cycle. Our initial genome-wide screening approach for copy number variants (CNVs) in ADHD implicated a duplication of SLC2A3, encoding glucose transporter-3 (GLUT3). GLUT3 plays a critical role in cerebral glucose metabolism, providing energy for the activity of neurons, which, in turn, moderates the excitatory-inhibitory balance impacting both brain development and activity-dependent neural plasticity. We therefore aimed to provide additional genetic and functional evidence for GLUT3 dysfunction in ADHD. Case-control association analyses of SLC2A3 single-nucleotide polymorphisms (SNPs) and CNVs were conducted in several European cohorts of patients with childhood and adult ADHD (SNP, n = 1,886 vs. 1,988; CNV, n = 1,692 vs. 1,721). These studies were complemented by SLC2A3 expression analyses in peripheral cells, functional EEG recordings during neurocognitive tasks, and ratings of food energy content. Meta-analysis of all cohorts detected an association of SNP rs12842 with ADHD. While CNV analysis detected a population-specific enrichment of SLC2A3 duplications only in German ADHD patients, the CNV + rs12842 haplotype influenced ADHD risk in both the German and Spanish cohorts. Duplication carriers displayed elevated SLC2A3 mRNA expression in peripheral blood cells and altered event-related potentials reflecting deficits in working memory and cognitive response control, both endophenotypic traits of ADHD, and an underestimation of energy units of high-caloric food. Taken together, our results indicate that both common and rare SLC2A3 variation impacting regulation of neuronal glucose utilization and energy homeostasis may result in neurocognitive deficits known to contribute to ADHD risk. © 2017 Association for Child and Adolescent Mental Health.

Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2

PubMed Central

Foley, A. Reghan; Menezes, Manoj P.; Pandraud, Amelie; Gonzalez, Michael A.; Al-Odaib, Ahmad; Abrams, Alexander J.; Sugano, Kumiko; Yonezawa, Atsushi; Manzur, Adnan Y.; Burns, Joshua; Hughes, Imelda; McCullagh, B. Gary; Jungbluth, Heinz; Lim, Ming J.; Lin, Jean-Pierre; Megarbane, Andre; Urtizberea, J. Andoni; Shah, Ayaz H.; Antony, Jayne; Webster, Richard; Broomfield, Alexander; Ng, Joanne; Mathew, Ann A.; O’Byrne, James J.; Forman, Eva; Scoto, Mariacristina; Prasad, Manish; O’Brien, Katherine; Olpin, Simon; Oppenheim, Marcus; Hargreaves, Iain; Land, John M.; Wang, Min X.; Carpenter, Kevin; Horvath, Rita; Straub, Volker; Lek, Monkol; Gold, Wendy; Farrell, Michael O.; Brandner, Sebastian; Phadke, Rahul; Matsubara, Kazuo; McGarvey, Michael L.; Scherer, Steven S.; Baxter, Peter S.; King, Mary D.; Clayton, Peter; Rahman, Shamima; Reilly, Mary M.; Ouvrier, Robert A.; Christodoulou, John; Züchner, Stephan; Muntoni, Francesco

2014-01-01

Childhood onset motor neuron diseases or neuronopathies are a clinically heterogeneous group of disorders. A particularly severe subgroup first described in 1894, and subsequently called Brown-Vialetto-Van Laere syndrome, is characterized by progressive pontobulbar palsy, sensorineural hearing loss and respiratory insufficiency. There has been no treatment for this progressive neurodegenerative disorder, which leads to respiratory failure and usually death during childhood. We recently reported the identification of SLC52A2, encoding riboflavin transporter RFVT2, as a new causative gene for Brown-Vialetto-Van Laere syndrome. We used both exome and Sanger sequencing to identify SLC52A2 mutations in patients presenting with cranial neuropathies and sensorimotor neuropathy with or without respiratory insufficiency. We undertook clinical, neurophysiological and biochemical characterization of patients with mutations in SLC52A2, functionally analysed the most prevalent mutations and initiated a regimen of high-dose oral riboflavin. We identified 18 patients from 13 families with compound heterozygous or homozygous mutations in SLC52A2. Affected individuals share a core phenotype of rapidly progressive axonal sensorimotor neuropathy (manifesting with sensory ataxia, severe weakness of the upper limbs and axial muscles with distinctly preserved strength of the lower limbs), hearing loss, optic atrophy and respiratory insufficiency. We demonstrate that SLC52A2 mutations cause reduced riboflavin uptake and reduced riboflavin transporter protein expression, and we report the response to high-dose oral riboflavin therapy in patients with SLC52A2 mutations, including significant and sustained clinical and biochemical improvements in two patients and preliminary clinical response data in 13 patients with associated biochemical improvements in 10 patients. The clinical and biochemical responses of this SLC52A2-specific cohort suggest that riboflavin supplementation can ameliorate the progression of this neurodegenerative condition, particularly when initiated soon after the onset of symptoms. PMID:24253200

Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2.

PubMed

Foley, A Reghan; Menezes, Manoj P; Pandraud, Amelie; Gonzalez, Michael A; Al-Odaib, Ahmad; Abrams, Alexander J; Sugano, Kumiko; Yonezawa, Atsushi; Manzur, Adnan Y; Burns, Joshua; Hughes, Imelda; McCullagh, B Gary; Jungbluth, Heinz; Lim, Ming J; Lin, Jean-Pierre; Megarbane, Andre; Urtizberea, J Andoni; Shah, Ayaz H; Antony, Jayne; Webster, Richard; Broomfield, Alexander; Ng, Joanne; Mathew, Ann A; O'Byrne, James J; Forman, Eva; Scoto, Mariacristina; Prasad, Manish; O'Brien, Katherine; Olpin, Simon; Oppenheim, Marcus; Hargreaves, Iain; Land, John M; Wang, Min X; Carpenter, Kevin; Horvath, Rita; Straub, Volker; Lek, Monkol; Gold, Wendy; Farrell, Michael O; Brandner, Sebastian; Phadke, Rahul; Matsubara, Kazuo; McGarvey, Michael L; Scherer, Steven S; Baxter, Peter S; King, Mary D; Clayton, Peter; Rahman, Shamima; Reilly, Mary M; Ouvrier, Robert A; Christodoulou, John; Züchner, Stephan; Muntoni, Francesco; Houlden, Henry

2014-01-01

Childhood onset motor neuron diseases or neuronopathies are a clinically heterogeneous group of disorders. A particularly severe subgroup first described in 1894, and subsequently called Brown-Vialetto-Van Laere syndrome, is characterized by progressive pontobulbar palsy, sensorineural hearing loss and respiratory insufficiency. There has been no treatment for this progressive neurodegenerative disorder, which leads to respiratory failure and usually death during childhood. We recently reported the identification of SLC52A2, encoding riboflavin transporter RFVT2, as a new causative gene for Brown-Vialetto-Van Laere syndrome. We used both exome and Sanger sequencing to identify SLC52A2 mutations in patients presenting with cranial neuropathies and sensorimotor neuropathy with or without respiratory insufficiency. We undertook clinical, neurophysiological and biochemical characterization of patients with mutations in SLC52A2, functionally analysed the most prevalent mutations and initiated a regimen of high-dose oral riboflavin. We identified 18 patients from 13 families with compound heterozygous or homozygous mutations in SLC52A2. Affected individuals share a core phenotype of rapidly progressive axonal sensorimotor neuropathy (manifesting with sensory ataxia, severe weakness of the upper limbs and axial muscles with distinctly preserved strength of the lower limbs), hearing loss, optic atrophy and respiratory insufficiency. We demonstrate that SLC52A2 mutations cause reduced riboflavin uptake and reduced riboflavin transporter protein expression, and we report the response to high-dose oral riboflavin therapy in patients with SLC52A2 mutations, including significant and sustained clinical and biochemical improvements in two patients and preliminary clinical response data in 13 patients with associated biochemical improvements in 10 patients. The clinical and biochemical responses of this SLC52A2-specific cohort suggest that riboflavin supplementation can ameliorate the progression of this neurodegenerative condition, particularly when initiated soon after the onset of symptoms.

Reduced Slc1a1 expression is associated with neuroinflammation and impaired sensorimotor gating and cognitive performance in mice: Implications for schizophrenia

PubMed Central

Afshari, Parisa; Yao, Wei-Dong

2017-01-01

We previously reported a 84-Kb hemi-deletion copy number variant at the SLC1A1 gene locus that reduces its expression and appeared causally linked to schizophrenia. In this report, we characterize the in vivo and in vitro consequences of reduced expression of Slc1a1 in mice. Heterozygous (HET) Slc1a1+/- mice, which more closely model the hemi-deletion we found in human subjects, were examined in a series of behavioral, anatomical and biochemical assays. Knockout (KO) mice were also included in the behavioral studies for comparative purposes. Both HET and KO mice exhibited evidence of increased anxiety-like behavior, impaired working memory, decreased exploratory activity and impaired sensorimotor gating, but no changes in overall locomotor activity. The magnitude of changes was approximately equivalent in the HET and KO mice suggesting a dominant effect of the haploinsufficiency. Behavioral changes in the HET mice were accompanied by reduced thickness of the dorsomedial prefrontal cortex. Whole transcriptome RNA-Seq analysis detected expression changes of genes and pathways involved in cytokine signaling and synaptic functions in both brain and blood. Moreover, the brains of Slc1a1+/- mice displayed elevated levels of oxidized glutathione, a trend for increased oxidative DNA damage, and significantly increased levels of cytokines. This latter finding was further supported by SLC1A1 knockdown and overexpression studies in differentiated human neuroblastoma cells, which led to decreased or increased cytokine expression, respectively. Taken together, our results suggest that partial loss of the Slc1a1 gene in mice causes haploinsufficiency associated with behavioral, histological and biochemical changes that reflect an altered redox state and may promote the expression of behavioral features and inflammatory states consistent with those observed in schizophrenia. PMID:28886095

Expression Levels of KMT2C and SLC20A1 Identified by Information-theoretical Analysis Are Powerful Prognostic Biomarkers in Estrogen Receptor-positive Breast Cancer.

PubMed

Sato, Keiko; Akimoto, Kazunori

2017-06-01

In general, it has been considered that estrogen receptor-positive (ER + ) breast cancer has a good prognosis and is responsive to endocrine therapy. However, one third of patients with ER + breast cancer exhibit endocrine therapy resistance, and many patients develop recurrence and die 5 to 10 years after diagnosis. In ER +  breast cancer, a major problem is to distinguish those patients most likely to develop recurrence or metastatic disease within 10 years after diagnosis from those with a sufficiently good prognosis. We downloaded the messenger RNA expression data and the clinical information for 401 patients with ER +  breast cancer from the cBioPortal for Cancer Genomics. An information-theoretical approach was used to identify the prognostic factors for survival in patients with ER + breast cancer and to classify those patients according to the prognostic factors. The information-theoretical approach contributed to the identification of KMT2C and SLC20A1 as prognostic biomarkers in ER + breast cancer. We found that low KMT2C expression was associated with a poor outcome and high SLC20A1 expression was associated with a poor outcome. Both levels of KMT2C and SLC20A1 expression were significantly and strongly associated with the differentiation of survival. The 10-year survival rate for ER + patients with low KMT2C and high SLC20A1 expression was 0%. In contrast, for ER + patients with high KMT2C and low SLC20A1 expression, the 10-year survival rate was 86.78%. Our results strongly suggest that clinical examination of the expression of both KMT2C and SLC20A1 in ER + breast cancer will be very useful for the determination of prognosis and therapy. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

A 40-bp VNTR polymorphism in the 3'-untranslated region of DAT1/SLC6A3 is associated with ADHD but not with alcoholism.

PubMed

Šerý, Omar; Paclt, Ivo; Drtílková, Ivana; Theiner, Pavel; Kopečková, Marta; Zvolský, Petr; Balcar, Vladimir J

2015-06-11

ADHD and alcoholism are psychiatric diseases with pathophysiology related to dopamine system. DAT1 belongs to the SLC6 family of transporters and is involved in the regulation of extracellular dopamine levels. A 40 bp variable number tandem repeat (VNTR) polymorphism in the 3'-untranslated region of DAT1/SLC6A3 gene was previously reported to be associated with various phenotypes involving disturbed regulation of dopaminergic neurotransmission. A total of 1312 subjects were included and genotyped for 40 bp VNTR polymorphism of DAT1/SLC6A3 gene in this study (441 alcoholics, 400 non-alcoholic controls, 218 ADHD children and 253 non ADHD children). Using miRBase software, we have performed a computer analysis of VNTR part of DAT1 gene for presence of miRNA binding sites. We have found significant relationships between ADHD and the 40 bp VNTR polymorphisms of DAT1/SLC6A3 gene (P < 0.01). The 9/9 genotype appeared to reduce the risk of ADHD about 0.4-fold (p < 0.04). We also noted an occurrence of rare genotypes in ADHD (frequency different from controls at p < 0.01). No association between alcoholism and genotype frequencies of 40 bp VNTR polymorphism of DAT1/SLC6A3 gene has been detected. We have found an association between 40 bp VNTR polymorphism of DAT1/SLC6A3 gene and ADHD in the Czech population; in a broad agreement with studies in other population samples. Furthermore, we detected rare genotypes 8/10, 7/10 and 10/11 present in ADHD boys only and identified miRNAs that should be looked at as potential novel targets in the research on ADHD.

Radiation absorbed dose to bladder walls from positron emitters in the bladder content.

PubMed

Powell, G F; Chen, C T

1987-01-01

A method to calculate absorbed doses at depths in the walls of a static spherical bladder from a positron emitter in the bladder content has been developed. The beta ray dose component is calculated for a spherical model by employing the solutions to the integration of Loevinger and Bochkarev point source functions over line segments and a line segment source array technique. The gamma ray dose is determined using the specific gamma ray constant. As an example, absorbed radiation doses to the bladder walls from F-18 in the bladder content are presented for static spherical bladder models having radii of 2.0 and 3.5 cm, respectively. Experiments with ultra-thin thermoluminescent dosimeters (TLD's) were performed to verify the results of the calculations. Good agreement between TLD measurements and calculations was obtained.

Upgrade of the Surface Spectrometer at NEPOMUC for PAES, XPS and STM Investigations

NASA Astrophysics Data System (ADS)

Zimnik, S.; Lippert, F.; Hugenschmidt, C.

2014-04-01

The characterization of the elemental composition of surfaces is of great importance for the understanding of many surface processes, such as surface segregation or oxidation. Positron-annihilation-induced Auger Electron Spectroscopy (PAES) is a powerful technique for gathering information about the elemental composition of only the topmost atomic layer of a sample. The upgraded surface spectrometer at NEPOMUC (NEtron induced POsitron source MUniCh) enables a comprehensive surface analysis with the complementary techniques STM, XPS and PAES. A new X-ray source for X-ray induced photoelectron spectroscopy (XPS) was installed to gather additional information on oxidation states. A new scanning tunneling microscope (STM) is used as a complementary method to investigate with atomic resolution the surface electron density. The combination of PAES, XPS and STM allows the characterization of both the elemental composition, and the surface topology.

6. VIEW OF SLC3W CONTROL ROOM (ROOM 105) FROM ITS ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

6. VIEW OF SLC-3W CONTROL ROOM (ROOM 105) FROM ITS SOUTHEAST CORNER - Vandenberg Air Force Base, Space Launch Complex 3, Launch Operations Building, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

83. DETAIL OF HONEYWELL AIRCONDITIONING CONTROLS IN SLC3E CONTROL ROOM ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

83. DETAIL OF HONEYWELL AIR-CONDITIONING CONTROLS IN SLC-3E CONTROL ROOM - Vandenberg Air Force Base, Space Launch Complex 3, Launch Operations Building, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

9. Photocopy of engineering drawing. SECURITY UPGRADES, SLC17: PLANS, SECTIONS, ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

9. Photocopy of engineering drawing. SECURITY UPGRADES, SLC17: PLANS, SECTIONS, AND DETAILS, JANUARY 1993. - Cape Canaveral Air Station, Launch Complex 17, Facility 28425, East end of Lighthouse Road, Cape Canaveral, Brevard County, FL

8. Photocopy of engineering drawing. SECURITY UPGRADES, SLC17: ELEVATIONS AND ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

8. Photocopy of engineering drawing. SECURITY UPGRADES, SLC17: ELEVATIONS AND BUILDING SECTION, JULY 1992. - Cape Canaveral Air Station, Launch Complex 17, Facility 28425, East end of Lighthouse Road, Cape Canaveral, Brevard County, FL

Structural and mechanistic basis of proton-coupled metal ion transport in the SLC11/NRAMP family

PubMed Central

Ehrnstorfer, Ines A.; Manatschal, Cristina; Arnold, Fabian M.; Laederach, Juerg; Dutzler, Raimund

2017-01-01

Secondary active transporters of the SLC11/NRAMP family catalyse the uptake of iron and manganese into cells. These proteins are highly conserved across all kingdoms of life and thus likely share a common transport mechanism. Here we describe the structural and functional properties of the prokaryotic SLC11 transporter EcoDMT. Its crystal structure reveals a previously unknown outward-facing state of the protein family. In proteoliposomes EcoDMT mediates proton-coupled uptake of manganese at low micromolar concentrations. Mutants of residues in the transition-metal ion-binding site severely affect transport, whereas a mutation of a conserved histidine located near this site results in metal ion transport that appears uncoupled to proton transport. Combined with previous results, our study defines the conformational changes underlying transition-metal ion transport in the SLC11 family and it provides molecular insight to its coupling to protons. PMID:28059071

Borate transporter SLC4A11 mutations cause both Harboyan syndrome and non‐syndromic corneal endothelial dystrophy

PubMed Central

Desir, Julie; Moya, Graciela; Reish, Orit; Van Regemorter, Nicole; Deconinck, Hilde; David, Karen L; Meire, Françoise M; Abramowicz, Marc J

2007-01-01

Harboyan syndrome, or corneal dystrophy and perceptive deafness (CDPD), consists of congenital corneal endothelial dystrophy and progressive perceptive deafness, and is transmitted as an autosomal recessive trait. CDPD and autosomal recessive, non‐syndromic congenital hereditary endothelial corneal dystrophy (CHED2) both map at overlapping loci at 20p13, and mutations of SLC4A11 were reported recently in CHED2. A genotype study on six families with CDPD and on one family with either CHED or CDPD, from various ethnic backgrounds (in the seventh family, hearing loss could not be assessed because of the proband's young age), is reported here. Novel SLC4A11 mutations were found in all patients. Why some mutations cause hearing loss in addition to corneal dystrophy is presently unclear. These findings extend the implication of the SLC4A11 borate transporter beyond corneal dystrophy to perceptive deafness. PMID:17220209

SLC4 family transporters in a marine diatom directly pump bicarbonate from seawater

PubMed Central

Nakajima, Kensuke; Tanaka, Atsuko; Matsuda, Yusuke

2013-01-01

Photosynthesis in marine diatoms is a vital fraction of global primary production empowered by CO2-concentrating mechanisms. Acquisition of HCO3− from seawater is a critical primary step of the CO2-concentrating mechanism, allowing marine photoautotrophic eukaryotes to overcome CO2 limitation in alkaline high-salinity water. However, little is known about molecular mechanisms governing this process. Here, we show the importance of a plasma membrane-type HCO3− transporter for CO2 acquisition in a marine diatom. Ten putative solute carrier (SLC) family HCO3− transporter genes were found in the genome of the marine pennate diatom Phaeodactylum tricornutum. Homologs also exist in marine centric species, Thalassiosira pseudonana, suggesting a general occurrence of SLC transporters in marine diatoms. Seven genes were found to encode putative mammalian-type SLC4 family transporters in P. tricornutum, and three of seven genes were specifically transcribed under low CO2 conditions. One of these gene products, PtSLC4-2, was localized at the plasmalemma and significantly stimulated both dissolved inorganic carbon (DIC) uptake and photosynthesis in P. tricornutum. DIC uptake by PtSLC4-2 was efficiently inhibited by an anion-exchanger inhibitor, 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid, in a concentration-dependent manner and highly dependent on Na+ ions at concentrations over 100 mM. These results show that DIC influx into marine diatoms is directly driven at the plasmalemma by a specific HCO3− transporter with a significant halophilic nature. PMID:23297242

High rates of intestinal bicarbonate secretion in seawater tilapia (Oreochromis mossambicus).

PubMed

Ruiz-Jarabo, I; Gregório, S F; Gaetano, P; Trischitta, F; Fuentes, J

2017-05-01

Osmoregulation in fish is a complex process that requires the orchestrated cooperation of many tissues. In fish facing hyperosmotic environments, the intestinal absorption of some monovalent ions and the secretion of bicarbonate are key processes to favor water absorption. In the present study, we showed that bicarbonate levels in the intestinal fluid are several fold higher in seawater than in freshwater acclimated tilapia (Oreochromis mossambicus). In addition, we analyzed gene expression of the main molecular mechanisms involved in HCO 3 - movements i.e. slc26a6, slc26a3, slc4a4 and v-type H-ATPase sub C in the intestine of tilapia acclimated to both seawater and freshwater. Our results show an anterior/posterior functional regionalization of the intestine in tilapia in terms of expression patterns, which is affected by environmental salinity mostly in the anterior and mid intestine. Analysis of bicarbonate secretion using pH-Stat in tissues mounted in Ussing chambers reveals high rates of bicarbonate secretion in tilapia acclimated to seawater from anterior intestine to rectum ranging between ~900 and ~1700nmolHCO 3 - cm -2 h -1 . However, a relationship between the expression of slc26a6, slc26a3, slc4a4 and the rate of bicarbonate secretion seems to be compromised in the rectum. In this region, the low expression of the bicarbonate transporters could not explain the high bicarbonate secretion rates here described. However, we postulate that the elevated v-type H-ATPase mRNA expression in the rectum could be involved in this process. Copyright © 2017 Elsevier Inc. All rights reserved.

Homozygous SLC6A17 mutations cause autosomal-recessive intellectual disability with progressive tremor, speech impairment, and behavioral problems.

PubMed

Iqbal, Zafar; Willemsen, Marjolein H; Papon, Marie-Amélie; Musante, Luciana; Benevento, Marco; Hu, Hao; Venselaar, Hanka; Wissink-Lindhout, Willemijn M; Vulto-van Silfhout, Anneke T; Vissers, Lisenka E L M; de Brouwer, Arjan P M; Marouillat, Sylviane; Wienker, Thomas F; Ropers, Hans Hilger; Kahrizi, Kimia; Nadif Kasri, Nael; Najmabadi, Hossein; Laumonnier, Frédéric; Kleefstra, Tjitske; van Bokhoven, Hans

2015-03-05

We report on Dutch and Iranian families with affected individuals who present with moderate to severe intellectual disability and additional phenotypes including progressive tremor, speech impairment, and behavioral problems in certain individuals. A combination of exome sequencing and homozygosity mapping revealed homozygous mutations c.484G>A (p.Gly162Arg) and c.1898C>G (p.Pro633Arg) in SLC6A17. SLC6A17 is predominantly expressed in the brain, encodes a synaptic vesicular transporter of neutral amino acids and glutamate, and plays an important role in the regulation of glutamatergic synapses. Prediction programs and 3D modeling suggest that the identified mutations are deleterious to protein function. To directly test the functional consequences, we investigated the neuronal subcellular localization of overexpressed wild-type and mutant variants in mouse primary hippocampal neuronal cells. Wild-type protein was present in soma, axons, dendrites, and dendritic spines. p.Pro633Arg altered SLC6A17 was found in soma and proximal dendrites but did not reach spines. p.Gly162Arg altered SLC6A17 showed a normal subcellular distribution but was associated with an abnormal neuronal morphology mainly characterized by the loss of dendritic spines. In summary, our genetic findings implicate homozygous SLC6A17 mutations in autosomal-recessive intellectual disability, and their pathogenic role is strengthened by genetic evidence and in silico and in vitro functional analyses. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Expression profiling of the solute carrier gene family in chicken intestine from the late embryonic to early post-hatch stages.

PubMed

Li, H; Gilbert, E R; Zhang, Y; Crasta, O; Emmerson, D; Webb, K E; Wong, E A

2008-08-01

Intestinal development during late embryogenesis and early post-hatch has a long-term influence on digestive and absorptive capacity in chickens. The objective of this research was to obtain a global view of intestinal solute carrier (SLC) gene family member expression from late embryogenesis until 2 weeks post-hatch with a focus on SLC genes involved in uptake of sugars and amino acids. Small intestine samples from male chicks were collected on embryonic days 18 (E18) and 20 (E20), day of hatch and days 1, 3, 7 and 14 post-hatch. The expression profiles of 162 SLC genes belonging to 41 SLC families were determined using Affymetrix chicken genome microarrays. The majority of SLC genes showed little or no difference in level of expression during E18-D14. A number of well-known intestinal transporters were upregulated between E18 and D14 including the amino acid transporters rBAT, y(+)LAT-2 and EAAT3, the peptide transporter PepT1 and the sugar transporters SGLT1, GLUT2 and GLUT5. The amino acid transporters CAT-1 and CAT-2 were downregulated. In addition, several glucose and amino acid transporters that are novel to our understanding of nutrient absorption in the chicken intestine were discovered through the arrays (SGLT6, SNAT1, SNAT2 and AST). These results represent a comprehensive characterization of the expression profiles of the SLC family of genes at different stages of development in the chicken intestine and lay the ground work for future nutritional studies.

Teleost fish models in membrane transport research: the PEPT1(SLC15A1) H+–oligopeptide transporter as a case study

PubMed Central

Romano, Alessandro; Barca, Amilcare; Storelli, Carlo; Verri, Tiziano

2014-01-01

Human genes for passive, ion-coupled transporters and exchangers are included in the so-called solute carrier (SLC) gene series, to date consisting of 52 families and 398 genes. Teleost fish genes for SLC proteins have also been described in the last two decades, and catalogued in preliminary SLC-like form in 50 families and at least 338 genes after systematic GenBank database mining (December 2010–March 2011). When the kinetic properties of the expressed proteins are studied in detail, teleost fish SLC transporters always reveal extraordinary ‘molecular diversity’ with respect to the mammalian counterparts, which reflects peculiar adaptation of the protein to the physiology of the species and/or to the environment where the species lives. In the case of the H+–oligopeptide transporter PEPT1(SLC15A1), comparative analysis of diverse teleost fish orthologs has shown that the protein may exhibit very eccentric properties in terms of pH dependence (e.g. the adaptation of zebrafish PEPT1 to alkaline pH), temperature dependence (e.g. the adaptation of icefish PEPT1 to sub-zero temperatures) and/or substrate specificity (e.g. the species-specificity of PEPT1 for the uptake of l-lysine-containing peptides). The revelation of such peculiarities is providing new contributions to the discussion on PEPT1 in both basic (e.g. molecular structure–function analyses) and applied research (e.g. optimizing diets to enhance growth of commercially valuable fish). PMID:23981715

Novel synthesis of nanocomposite for the extraction of Sildenafil Citrate (Viagra) from water and urine samples: Process screening and optimization.

PubMed

Asfaram, Arash; Ghaedi, Mehrorang; Purkait, Mihir Kumar

2017-09-01

A sensitive analytical method is investigated to concentrate and determine trace level of Sildenafil Citrate (SLC) present in water and urine samples. The method is based on a sample treatment using dispersive solid-phase micro-extraction (DSPME) with laboratory-made Mn@ CuS/ZnS nanocomposite loaded on activated carbon (Mn@ CuS/ZnS-NCs-AC) as a sorbent for the target analyte. The efficiency was enhanced by ultrasound-assisted (UA) with dispersive nanocomposite solid-phase micro-extraction (UA-DNSPME). Four significant variables affecting SLC recovery like; pH, eluent volume, sonication time and adsorbent mass were selected by the Plackett-Burman design (PBD) experiments. These selected factors were optimized by the central composite design (CCD) to maximize extraction of SLC. The results exhibited that the optimum conditions for maximizing extraction of SLC were 6.0 pH, 300μL eluent (acetonitrile) volume, 10mg of adsorbent and 6min sonication time. Under optimized conditions, virtuous linearity of SLC was ranged from 30 to 4000ngmL -1 with R 2 of 0.99. The limit of detection (LOD) was 2.50ngmL -1 and the recoveries at two spiked levels were ranged from 97.37 to 103.21% with the relative standard deviation (RSD) less than 4.50% (n=15). The enhancement factor (EF) was 81.91. The results show that the combination UAE with DNSPME is a suitable method for the determination of SLC in water and urine samples. Copyright © 2017 Elsevier B.V. All rights reserved.

Glutamine Transporters in Mammalian Cells and Their Functions in Physiology and Cancer

PubMed Central

Bhutia, Yangzom D.; Ganapathy, Vadivel

2016-01-01

The SLC (solute carrier)-type transporters (∼400 in number) in mammalian cells consist of 52 distinct gene families, grouped solely based on the amino acid sequence (primary structure) of the transporter proteins and not on their transport function. Among them are the transporters for amino acids. Fourteen of them, capable of transporting glutamine across the plasma membrane, are found in four families: SLC1, SLC6, SLC7, and SLC38. However, it is generally thought that the members of the SLC38 family are the principal transporters for glutamine. Some of the glutamine transporters are obligatory exchangers whereas some function as active transporters in one direction. While most glutamine transporters mediate the influx of the amino acid into cells, some actually mediate the efflux of the amino acid out of the cells. Glutamine transporters play important roles in a variety of tissues, including the liver, brain, kidney, and placenta, as clearly evident from the biological and biochemical phenotypes resulting from the deletion of specific glutamine transporters in mice. Owing to the obligatory role of glutamine in growth and proliferation of tumor cells, there is increasing attention on glutamine transporters in cancer biology as potential drug targets for cancer treatment. Selective blockers of certain glutamine transporters might be effective in preventing the entry of glutamine and other important amino acids into tumor cells, thus essentially starving these cells to death. This could represent the beginning of a new era in the discovery of novel anticancer drugs with a previously unexplored mode of action. PMID:26724577

Mutation Analysis of SLC26A4 for Pendred Syndrome and Nonsyndromic Hearing Loss by High-Resolution Melting

PubMed Central

Chen, Neng; Tranebjærg, Lisbeth; Rendtorff, Nanna Dahl; Schrijver, Iris

2011-01-01

Pendred syndrome and DFNB4 (autosomal recessive nonsyndromic congenital deafness, locus 4) are associated with autosomal recessive congenital sensorineural hearing loss and mutations in the SLC26A4 gene. Extensive allelic heterogeneity, however, necessitates analysis of all exons and splice sites to identify mutations for individual patients. Although Sanger sequencing is the gold standard for mutation detection, screening methods supplemented with targeted sequencing can provide a cost-effective alternative. One such method, denaturing high-performance liquid chromatography, was developed for clinical mutation detection in SLC26A4. However, this method inherently cannot distinguish homozygous changes from wild-type sequences. High-resolution melting (HRM), on the other hand, can detect heterozygous and homozygous changes cost-effectively, without any post-PCR modifications. We developed a closed-tube HRM mutation detection method specific for SLC26A4 that can be used in the clinical diagnostic setting. Twenty-eight primer pairs were designed to cover all 21 SLC26A4 exons and splice junction sequences. Using the resulting amplicons, initial HRM analysis detected all 45 variants previously identified by sequencing. Subsequently, a 384-well plate format was designed for up to three patient samples per run. Blinded HRM testing on these plates of patient samples collected over 1 year in a clinical diagnostic laboratory accurately detected all variants identified by sequencing. In conclusion, HRM with targeted sequencing is a reliable, simple, and cost-effective method for SLC26A4 mutation screening and detection. PMID:21704276

Molecular cloning, mRNA expression and tissue distribution analysis of Slc7a11 gene in alpaca (Lama paco) skins associated with different coat colors.

PubMed

Tian, Xue; Meng, Xiaolin; Wang, Liangyan; Song, Yunfei; Zhang, Danli; Ji, Yuankai; Li, Xuejun; Dong, Changsheng

2015-01-25

Slc7a11 encoding solute carrier family 7 member 11 (amionic amino acid transporter light chain, xCT), has been identified to be a critical genetic regulator of pheomelanin synthesis in hair and melanocytes. To better understand the molecular characterization of Slc7a11 and the expression patterns in skin of white versus brown alpaca (lama paco), we cloned the full length coding sequence (CDS) of alpaca Slc7a11 gene and analyzed the expression patterns using Real Time PCR, Western blotting and immunohistochemistry. The full length CDS of 1512bp encodes a 503 amino acid polypeptide. Sequence analysis showed that alpaca xCT contains 12 transmembrane regions consistent with the highly conserved amino acid permease (AA_permease_2) domain similar to other vertebrates. Sequence alignment and phylogenetic analysis revealed that alpaca xCT had the highest identity and shared the same branch with Camelus ferus. Real Time PCR and Western blotting suggested that xCT was expressed at significantly high levels in brown alpaca skin, and transcripts and protein possessed the same expression pattern in white and brown alpaca skins. Additionally, immunohistochemical analysis further demonstrated that xCT staining was robustly increased in the matrix and root sheath of brown alpaca skin compared with that of white. These results suggest that Slc7a11 functions in alpaca coat color regulation and offer essential information for further exploration on the role of Slc7a11 in melanogenesis. Copyright © 2014 Elsevier B.V. All rights reserved.

Dust Ion-Acoustic Shock Waves in a Multicomponent Magnetorotating Plasma

NASA Astrophysics Data System (ADS)

Kaur, Barjinder; Saini, N. S.

2018-02-01

The nonlinear properties of dust ion-acoustic (DIA) shock waves in a magnetorotating plasma consisting of inertial ions, nonextensive electrons and positrons, and immobile negatively charged dust are examined. The effects of dust charge fluctuations are not included in the present investigation, but the ion kinematic viscosity (collisions) is a source of dissipation, leading to the formation of stable shock structures. The Zakharov-Kuznetsov-Burgers (ZKB) equation is derived using the reductive perturbation technique, and from its solution the effects of different physical parameters, i.e. nonextensivity of electrons and positrons, kinematic viscosity, rotational frequency, and positron and dust concentrations, on the characteristics of shock waves are examined. It is observed that physical parameters play a very crucial role in the formation of DIA shocks. This study could be useful in understanding the electrostatic excitations in dusty plasmas in space (e.g. interstellar medium).

The Positronium Radiative Combination Spectrum: Calculation in the Limit of Thermal Positrons and Low Densities

NASA Technical Reports Server (NTRS)

Wallyn, P.; Mahoney, W. A.; Durouchoux, Ph.; Chapuis, C.

1996-01-01

We calculate the intensities of the positronium de-excitation lines for two processes: (1) the radiative combination of free thermal electrons and positrons for transitions with principal quantum number n less than 20, and (2) charge exchange between free positrons and hydrogen and helium atoms, restricting our evaluation to the Lyman-alpha line. We consider a low-density medium modeled by the case A assumption of Baker & Menzel and use the "nL method" of Pengelly to calculate the absolute intensities. We also evaluate the positronium fine and hyperfine intensities and show that these transitions are in all cases much weaker than positronium de-excitation lines in the same wavelength range. We also extrapolate our positronium de-excitation intensities to the submillimeter, millimeter, and centimeter wavelengths. Our results favor the search of infrared transitions of positronium lines for point sources when the visual extinction A, is greater than approx. 5.

Bruno Touschek: From Betatrons to Electron-Positron Colliders

NASA Astrophysics Data System (ADS)

Bernardini, Carlo; Pancheri, Giulia; Pellegrini, Claudio

Bruno Touschek's life as a physicist spanned the period from World War II to the 1970s. He was a key figure in the developments of electron-positron colliders and storage rings, and made important contributions to theoretical high energy physics. Storage rings, initially developed for high energy physics, are being widely used in many countries as synchrotron radiation sources and are a tool for research in physics, chemistry, biology, environmental sciences and cultural heritage studies. We describe Touschek's life in Austria, where he was born, in Germany, where he participated in the construction of a betatron during WWII, and in Italy, where he proposed and led to completion the first electron-positron storage ring in 1960, in Frascati. We highlight how his central European culture influenced his lifestyle and work, and his main contributions to physics, such as the discovery of the Touschek effect and beam instabilities in the larger storage ring ADONE.

Bruno Touschek: From Betatrons to Electron-Positron Colliders

NASA Astrophysics Data System (ADS)

Bernardini, Carlo; Pancheri, Giulia; Pellegrini, Claudio

Bruno Touschek’s life as a physicist spanned the period from World War II to the 1970s. He was a key figure in the developments of electron-positron colliders and storage rings, and made important contributions to theoretical high energy physics. Storage rings, initially developed for high energy physics, are being widely used in many countries as synchrotron radiation sources and are a tool for research in physics, chemistry, biology, environmental sciences and cultural heritage studies. We describe Touschek’s life in Austria, where he was born, in Germany, where he participated in the construction of a betatron during WWII, and in Italy, where he proposed and led to completion the first electron-positron storage ring in 1960, in Frascati. We highlight how his central European culture influenced his lifestyle and work, and his main contributions to physics, such as the discovery of the Touschek effect and beam instabilities in the larger storage ring ADONE.

Cerenkov radiation allows in vivo optical imaging of positron emitting radiotracers

NASA Astrophysics Data System (ADS)

Spinelli, Antonello E.; D'Ambrosio, Daniela; Calderan, Laura; Marengo, Mario; Sbarbati, Andrea; Boschi, Federico

2010-01-01

In this paper, we showed that Cerenkov radiation (CR) escaping from the surface of small living animals injected with 18F-FDG can be detected with optical imaging techniques. 18F decays by emitting positrons with a maximum energy of 0.635 MeV; such positrons, when travelling into tissues faster than the speed of light in the same medium, are responsible of CR emission. A detailed model of the CR spectrum considering the positron energy spectrum was developed in order to quantify the amount of light emission. The results presented in this work were obtained using a commercial optical imager equipped with charged coupled detectors (CCD). Our data open the door to optical imaging (OI) in vivo of the glucose metabolism, at least in pre-clinical research. We found that the heart and bladder can be clearly identified in the animal body reflecting the accumulation of the 18F-FDG. Moreover, we describe two different methods based on the spectral analysis of the CR that can be used to estimate the depth of the source inside the animal. We conclude that 18F-FDG can be employed as it is as a bimodal tracer for positron emission tomography (PET) and OI techniques. Our results are encouraging, suggesting that it could be possible to apply the proposed approach not only to β+ but also to pure β- emitters.

Cerenkov radiation allows in vivo optical imaging of positron emitting radiotracers.

PubMed

Spinelli, Antonello E; D'Ambrosio, Daniela; Calderan, Laura; Marengo, Mario; Sbarbati, Andrea; Boschi, Federico

2010-01-21

In this paper, we showed that Cerenkov radiation (CR) escaping from the surface of small living animals injected with (18)F-FDG can be detected with optical imaging techniques. (18)F decays by emitting positrons with a maximum energy of 0.635 MeV; such positrons, when travelling into tissues faster than the speed of light in the same medium, are responsible of CR emission. A detailed model of the CR spectrum considering the positron energy spectrum was developed in order to quantify the amount of light emission. The results presented in this work were obtained using a commercial optical imager equipped with charged coupled detectors (CCD). Our data open the door to optical imaging (OI) in vivo of the glucose metabolism, at least in pre-clinical research. We found that the heart and bladder can be clearly identified in the animal body reflecting the accumulation of the (18)F-FDG. Moreover, we describe two different methods based on the spectral analysis of the CR that can be used to estimate the depth of the source inside the animal. We conclude that (18)F-FDG can be employed as it is as a bimodal tracer for positron emission tomography (PET) and OI techniques. Our results are encouraging, suggesting that it could be possible to apply the proposed approach not only to beta(+) but also to pure beta(-) emitters.

Positron-induced Auger-electron study of the Ge(100) surface: Positron thermal desorption and surface condition

DOE Office of Scientific and Technical Information (OSTI.GOV)

Soininen, E.; Schwab, A.; Lynn, K.G.

1991-05-01

Positron-annihilation-induced Auger-electron spectroscopy (PAES) was used to study the effects of oxygen, residual gases, and temperature on a Ge(100) surface. Three low-energy Auger peaks were detected at 50, 90, and 100--150 eV, attributed to {ital M}{sub 2,3}{ital M4}{ital M4}, {ital M}{sub 2,3}{ital M4}{ital V}, and {ital M}{sub 1}{ital M4}{ital M4} Auger transitions, respectively. An estimated (4{plus minus}1)% of the surface-trapped positrons annihilate with Ge 3{ital p}--level electrons. The sensitivity of PAES to the surface condition is demonstrated. The PAES yield from a Ge(100) surface is reduced at elevated temperatures, in accord with an activation process earlier found in several positroniummore » (Ps) -fraction experiments. A desorption model adopted from these studies does not describe accurately the PAES results at higher temperatures ({gt}500 {degree}C), where the PAES intensity levels off to 5% of the room-temperature value. Possible sources for the discrepancy are discussed and models for positron trapping to deep surface traps are introduced. On the Ge(100) surface, an upper limit for Ps emission near the melting point is 97%. The error in calibration parameters due to the earlier assumption of 100% Ps emission seems to introduce only small errors into the Ps-fraction measurements.« less

11. CENTRAL ATLAS CONTROL CONSOLE IN SLC3W CONTROL ROOM. COMMUNICATIONS ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

11. CENTRAL ATLAS CONTROL CONSOLE IN SLC-3W CONTROL ROOM. COMMUNICATIONS HEADSETS IN FOREGROUND. - Vandenberg Air Force Base, Space Launch Complex 3, Launch Operations Building, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

Synthesis/literature review for determining structural layer coefficients (SLC) of bases.

DOT National Transportation Integrated Search

2014-12-01

FDOTs current method of determining a base material structural layer coefficient (SLC) is detailed in the : Materials Manual, Chapter 2.1, Structural Layer Coefficients for Flexible Pavement Base Materials. : Currently, any new base material not a...

Associating mutations causing cystinuria with disease severity with the aim of providing precision medicine.

PubMed

Martell, Henry J; Wong, Kathie A; Martin, Juan F; Kassam, Ziyan; Thomas, Kay; Wass, Mark N

2017-08-11

Cystinuria is an inherited disease that results in the formation of cystine stones in the kidney, which can have serious health complications. Two genes (SLC7A9 and SLC3A1) that form an amino acid transporter are known to be responsible for the disease. Variants that cause the disease disrupt amino acid transport across the cell membrane, leading to the build-up of relatively insoluble cystine, resulting in formation of stones. Assessing the effects of each mutation is critical in order to provide tailored treatment options for patients. We used various computational methods to assess the effects of cystinuria associated mutations, utilising information on protein function, evolutionary conservation and natural population variation of the two genes. We also analysed the ability of some methods to predict the phenotypes of individuals with cystinuria, based on their genotypes, and compared this to clinical data. Using a literature search, we collated a set of 94 SLC3A1 and 58 SLC7A9 point mutations known to be associated with cystinuria. There are differences in sequence location, evolutionary conservation, allele frequency, and predicted effect on protein function between these mutations and other genetic variants of the same genes that occur in a large population. Structural analysis considered how these mutations might lead to cystinuria. For SLC7A9, many mutations swap hydrophobic amino acids for charged amino acids or vice versa, while others affect known functional sites. For SLC3A1, functional information is currently insufficient to make confident predictions but mutations often result in the loss of hydrogen bonds and largely appear to affect protein stability. Finally, we showed that computational predictions of mutation severity were significantly correlated with the disease phenotypes of patients from a clinical study, despite different methods disagreeing for some of their predictions. The results of this study are promising and highlight the areas of research which must now be pursued to better understand how mutations in SLC3A1 and SLC7A9 cause cystinuria. The application of our approach to a larger data set is essential, but we have shown that computational methods could play an important role in designing more effective personalised treatment options for patients with cystinuria.

The D543N polymorphism of the SLC11A1/NRAMP1 gene is associated with treatment failure in male patients with pulmonary tuberculosis.

PubMed

Salinas-Delgado, Yvain; Galaviz-Hernández, Carlos; Toral, René García; Ávila Rejón, Carmen A; Reyes-Lopez, Miguel A; Martínez, Antonio Rojas; Martínez-Aguilar, Gerardo; Sosa-Macías, Martha

2015-09-01

Polymorphisms in SLC11A1/NRAMP1 have shown an important association with susceptibility to tuberculosis and progression to active disease. However, whether there is an association of these polymorphisms with treatment failure is unknown. The aim of this study was to determine the association of SLC11A1 polymorphisms with treatment failure in Mexican subjects with pulmonary tuberculosis. Thirty-three subjects with treatment failure were paired by age and body mass index with 33 patients who successfully completed treatment and were considered cured. We assessed the polymorphisms of SLC11A1 in the regions of D543N and INT4 via polymerase chain reaction real-time TaqMan® single nucleotide polymorphism (SNP) genotyping. We found that D543N (G/A genotype) was associated with treatment failure in patients with pulmonary tuberculosis [odds ratio (OR) 11.61, 95% confidence interval (CI) 3.66-36.78]. When adjusted by gender, this association remained significant in males (OR 11.09, 95% CI 3.46-35.51). In our male population, the presence of the D543N polymorphism of SLC11A1 is a risk factor for treatment failure. This finding should be confirmed in other populations.

Intellectual disability and bleeding diathesis due to deficient CMP--sialic acid transport.

PubMed

Mohamed, Miski; Ashikov, Angel; Guillard, Mailys; Robben, Joris H; Schmidt, Samuel; van den Heuvel, B; de Brouwer, Arjan P M; Gerardy-Schahn, Rita; Deen, Peter M T; Wevers, Ron A; Lefeber, Dirk J; Morava, Eva

2013-08-13

To identify the underlying genetic defect in a patient with intellectual disability, seizures, ataxia, macrothrombocytopenia, renal and cardiac involvement, and abnormal protein glycosylation. Genetic studies involved homozygosity mapping by 250K single nucleotide polymorphism array and SLC35A1 sequencing. Functional studies included biochemical assays for N-glycosylation and mucin-type O-glycosylation and SLC35A1-encoded cytidine 5'-monophosphosialic acid (CMP-sialic acid) transport after heterologous expression in yeast. We performed biochemical analysis and found combined N- and O-glycosylation abnormalities and specific reduction in sialylation in this patient. Homozygosity mapping revealed homozygosity for the CMP-sialic acid transporter SLC35A1. Mutation analysis identified a homozygous c.303G > C (p.Gln101His) missense mutation that was heterozygous in both parents. Functional analysis of mutant SLC35A1 showed normal Golgi localization but 50% reduction in transport activity of CMP-sialic acid in vitro. We confirm an autosomal recessive, generalized sialylation defect due to mutations in SLC35A1. The primary neurologic presentation consisting of ataxia, intellectual disability, and seizures, in combination with bleeding diathesis and proteinuria, is discriminative from a previous case described with deficient sialic acid transporter. Our study underlines the importance of sialylation for normal CNS development and regular organ function.

Stomatin interacts with GLUT1/SLC2A1, band 3/SLC4A1, and aquaporin-1 in human erythrocyte membrane domains

PubMed Central

Rungaldier, Stefanie; Oberwagner, Walter; Salzer, Ulrich; Csaszar, Edina; Prohaska, Rainer

2013-01-01

The widely expressed, homo-oligomeric, lipid raft-associated, monotopic integral membrane protein stomatin and its homologues are known to interact with and modulate various ion channels and transporters. Stomatin is a major protein of the human erythrocyte membrane, where it associates with and modifies the glucose transporter GLUT1; however, previous attempts to purify hetero-oligomeric stomatin complexes for biochemical analysis have failed. Because lateral interactions of membrane proteins may be short-lived and unstable, we have used in situ chemical cross-linking of erythrocyte membranes to fix the stomatin complexes for subsequent purification by immunoaffinity chromatography. To further enrich stomatin, we prepared detergent-resistant membranes either before or after cross-linking. Mass spectrometry of the isolated, high molecular, cross-linked stomatin complexes revealed the major interaction partners as glucose transporter-1 (GLUT1), anion exchanger (band 3), and water channel (aquaporin-1). Moreover, ferroportin-1 (SLC40A1), urea transporter-1 (SLC14A1), nucleoside transporter (SLC29A1), the calcium-pump (Ca-ATPase-4), CD47, and flotillins were identified as stomatin-interacting proteins. These findings are in line with the hypothesis that stomatin plays a role as membrane-bound scaffolding protein modulating transport proteins. PMID:23219802

The small SLC43 family: facilitator system l amino acid transporters and the orphan EEG1.

PubMed

Bodoy, Susanna; Fotiadis, Dimitrios; Stoeger, Claudia; Kanai, Yoshikatsu; Palacín, Manuel

2013-01-01

The SLC43 family is composed of only three genes coding for the plasma membrane facilitator system l amino acid transporters LAT3 (SLC43A1; TC 2.A.1.44.1) and LAT4 (SLC43A2; TC 2.A.1.44.2), and the orphan protein EEG1 (SLC43A3; TC 2.A.1.44.3). Besides the known mechanism of transport of LAT3 and LAT4, their physiological roles still remain quite obscure. Morphants suggested a role of LAT3 in renal podocyte development in zebrafish. Expression in liver and skeletal muscle, and up-regulation by starvation suggest a role of LAT3 in the flux of branched-chain amino acids (BCAAs) from liver and skeletal muscle to the bloodstream. Finally, LAT3 is up-regulated in androgen-dependent cancers, suggesting a role in mTORC1 signaling in this type of tumors. In addition, LAT4 might contribute to the transfer of BCAAs from mother to fetus. Unfortunately, the EEG1 mouse model (EEG1(Y221∗)) described here has not yet offered a clue to the physiological role of this orphan protein. Copyright © 2012 Elsevier Ltd. All rights reserved.

Obsessive-compulsive disorder and the promoter region polymorphism (5-HTTLPR) in the serotonin transporter gene (SLC6A4): a negative association study in the Afrikaner population.

PubMed

Kinnear, Craig J.; Niehaus, Dana J. H.; Moolman-Smook, Johanna C.; du Toit, Pieter L.; van Kradenberg, Jeanine; Weyers, Jakobus B.; Potgieter, Annemarie; Marais, Vanessa; Emsley, Robin A.; Knowles, James A.; Corfield, Valerie A.; Brink, Paul A.; Stein, Dan J.

2000-12-01

A polymorphism (5-HTTLPR) in the promoter region of the serotonin transporter gene (SLC6A4) has been reported to have functional significance and to be associated with obsessive-compulsive disorder (OCD). However, other studies have generated confounding results. A study was undertaken to re-evaluate this association in subjects drawn from the relatively genetically homogeneous Afrikaner population of South Africa. Fifty-four OCD patients of Afrikaner descent and 82 ethnically matched control individuals were phenotyped and genotyped. No significant association was found between the distribution of the 5-HTTLPR genotypes at the SLC6A4 locus and OCD. A similar result (p = 0.108) was generated when a meta-analysis of the 5-HTTLPR polymorphism, combining the current study with a previously reported Caucasian group, was performed; the meta-study comprised 129 OCD patients and 479 control individuals. However, both studies lacked power. Therefore, evidence that variation in SLC6A4 plays a significant role in the development of OCD in the population groups studied is inconclusive. Future association studies in Caucasian populations may extend the power of such meta-analyses and assist in delineating the role of SLC6A4 in OCD.

Pregnancy rates after artificial insemination with cooled stallion spermatozoa either with or without single layer centrifugation.

PubMed

Morrell, J M; Richter, J; Martinsson, G; Stuhtmann, G; Hoogewijs, M; Roels, K; Dalin, A-M

2014-11-01

A successful outcome after artificial insemination with cooled semen is dependent on many factors, the sperm quality of the ejaculate being one. Previous studies have shown that spermatozoa with good motility, normal morphology, and good chromatin integrity can be selected by means of colloid centrifugation, particularly single layer centrifugation (SLC) using species-specific colloids. The purpose of the present study was to conduct an insemination trial with spermatozoa from "normal" ejaculates, i.e., from stallions with no known fertility problem, to determine whether the improvements in sperm quality seen in SLC-selected sperm samples compared with uncentrifuged controls in laboratory tests are reflected in an increased pregnancy rate after artificial insemination. In a multicentre study, SLC-selected sperm samples and uncentrifuged controls from eight stallions were inseminated into approximately 10 mares per treatment per stallion. Ultrasound examination was carried out approximately 16 days after insemination to detect an embryonic vesicle. The pregnancy rates per cycle were 45% for controls and 69% for SLC-selected sperm samples, which is statistically significant (P < 0.0018). Thus, the improvement in sperm quality reported previously for SLC-selected sperm samples is associated with an increase in pregnancy rate, even for ejaculates from stallions with no known fertility problem. Copyright © 2014 Elsevier Inc. All rights reserved.

Molecular evolution of the Slc15 family and its response to waterborne copper and mercury exposure in tilapia.

PubMed

Huang, Qiansheng; Vera Delgado, Juan Manuel; Seni Pinoargote, Oscar David; Llaguno, Ricardo Avellán

2015-06-01

The solute carrier 15 family (Slc15), also called oligopeptide transporter family (Pept), was well-known for its role in the cellular uptake of di/tripeptides and peptide-like molecules. Our understanding of Slc15 family has already been enlarged since the rapid increasing of genome information; however, efforts are still expected to reveal the diversification of the family in an evolutionary manner. In the study, the sequence information were collected and analyzed through eleven eukaryotic organism representatives, especially in fish species. Gene expansion was observed through the evolution of the family. Further study was carried out with the representative species-Nile tilapia (Oreochromis niloticus). Tissue expression profiles were compared among members of the Slc15 family. Generally, they were all highly expressed both in the intestine and stomach, however, different members possessed its special tissue expression pattern. The mRNA levels of all the members (except Slc15a4) decreased after fasting while refeeding could restore the expression level. The recovery ability was impaired after exposure to environmental relevant concentration of copper (Cu(2+), 160 nmol/L). By contrast, mercury (Hg(2+), 25 nmol/L) did not exert significant impact on the recovery ability. Copyright © 2015 Elsevier B.V. All rights reserved.

Association of polymorphisms in 5-HTT (SLC6A4) and MAOA genes with measures of obesity in young adults of Portuguese origin.

PubMed

Dias, Helena; Muc, Magdalena; Padez, Cristina; Manco, Licínio

2016-01-01

To investigate the association of polymorphisms in SLC6A4 and MAOA genes with overweight (including obesity). Young adults (n = 535) of Portuguese origin were genotyped for the SLC6A4 polymorphisms 5-HTTLPR and STin2 and a MAOA VNTR. BMI and body fat percentage were measured and a questionnaire was used to assess individual's sport practicing habits. In whole study sample, haplotype-based analysis revealed significant association with overweight/obesity for the individual 5-HTTLPR/Stin2 haplotype L10 (p = 0.04). In men, the MAOA 3R genotype was nominally associated with body fat (p = 0.04). In inactive individuals, overweight/obesity was found significantly associated with 5-HTTLPR L-allele (p = 0.01) and nominally associated with STin2 10-allele (p = 0.03). A significant association was also found testing for all haplotype effects (χ(2 )= 8.7; p = 0.03). We found some evidences for the association of SLC6A4 and MAOA genes with measures of obesity. Our results suggest physical inactivity accentuates the influence of SLC6A4 polymorphisms on obesity risk.

SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome.

PubMed

Janer, Alexandre; Prudent, Julien; Paupe, Vincent; Fahiminiya, Somayyeh; Majewski, Jacek; Sgarioto, Nicolas; Des Rosiers, Christine; Forest, Anik; Lin, Zhen-Yuan; Gingras, Anne-Claude; Mitchell, Grant; McBride, Heidi M; Shoubridge, Eric A

2016-09-01

Mitochondria form a dynamic network that responds to physiological signals and metabolic stresses by altering the balance between fusion and fission. Mitochondrial fusion is orchestrated by conserved GTPases MFN1/2 and OPA1, a process coordinated in yeast by Ugo1, a mitochondrial metabolite carrier family protein. We uncovered a homozygous missense mutation in SLC25A46, the mammalian orthologue of Ugo1, in a subject with Leigh syndrome. SLC25A46 is an integral outer membrane protein that interacts with MFN2, OPA1, and the mitochondrial contact site and cristae organizing system (MICOS) complex. The subject mutation destabilizes the protein, leading to mitochondrial hyperfusion, alterations in endoplasmic reticulum (ER) morphology, impaired cellular respiration, and premature cellular senescence. The MICOS complex is disrupted in subject fibroblasts, resulting in strikingly abnormal mitochondrial architecture, with markedly shortened cristae. SLC25A46 also interacts with the ER membrane protein complex EMC, and phospholipid composition is altered in subject mitochondria. These results show that SLC25A46 plays a role in a mitochondrial/ER pathway that facilitates lipid transfer, and link altered mitochondrial dynamics to early-onset neurodegenerative disease and cell fate decisions. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

A missense mutation in solute carrier family 12, member 1 (SLC12A1) causes hydrallantois in Japanese Black cattle.

PubMed

Sasaki, Shinji; Hasegawa, Kiyotoshi; Higashi, Tomoko; Suzuki, Yutaka; Sugano, Sumio; Yasuda, Yasuaki; Sugimoto, Yoshikazu

2016-09-09

Hydrallantois is the excessive accumulation of fluid within the allantoic cavity in pregnant animals and is associated with fetal mortality. Although the incidence of hydrallantois is very low in artificial insemination breeding programs in cattle, recently 38 cows with the phenotypic appearance of hydrallantois were reported in a local subpopulation of Japanese Black cattle. Of these, 33 were traced back to the same sire; however, both their parents were reported healthy, suggesting that hydrallantois is a recessive inherited disorder. To identify autozygous chromosome segments shared by individuals with hydrallantois and the causative mutation in Japanese Black cattle, we performed autozygosity mapping using single-nucleotide polymorphism (SNP) array and exome sequencing. Shared haplotypes of the affected fetuses spanned 3.52 Mb on bovine chromosome 10. Exome sequencing identified a SNP (g.62382825G > A, p.Pro372Leu) in exon 10 of solute carrier family 12, member 1 (SLC12A1), the genotype of which was compatible with recessive inheritance. SLC12A1 serves as a reabsorption molecule of Na(+)-K(+)-2Cl(-) in the apical membrane of the thick ascending limb of the loop of Henle in the kidney. We observed that the concentration of Na(+)-Cl(-) increased in allantoic fluid of homozygous SLC12A1 (g.62382825G > A) in a hydrallantois individual. In addition, SLC12A1-positive signals were localized at the apical membrane in the kidneys of unaffected fetuses, whereas they were absent from the apical membrane in the kidneys of affected fetuses. These results suggested that p.Pro372Leu affects the membrane localization of SLC12A1, and in turn, may impair its transporter activity. Surveillance of the risk-allele frequency revealed that the carriers were restricted to the local subpopulation of Japanese Black cattle. Moreover, we identified a founder individual that carried the mutation (g.62382825G > A). In this study, we mapped the shared haplotypes of affected fetuses using autozygosity mapping and identified a de novo mutation in the SLC12A1 gene that was associated with hydrallantois in Japanese Black cattle. In kidneys of hydrallantois-affected fetuses, the mutation in SLC12A1 impaired the apical membrane localization of SLC12A1 and reabsorption of Na(+)-K(+)-2Cl(-) in the thick ascending limb of the loop of Henle, leading to a defect in the concentration of urine via the countercurrent mechanism. Consequently, the affected fetuses exhibited polyuria that accumulated in the allantoic cavity. Surveillance of the risk-allele frequency indicated that carriers were not widespread throughout the Japanese Black cattle population. Moreover, we identified the founder individual, and thus could effectively manage the disorder in the population.

Imaging Phenotypes of Major Depressive Disorder: Genetic Correlates

PubMed Central

Savitz, Jonathan B; Drevets, Wayne C

2009-01-01

Imaging techniques are a potentially powerful method of identifying phenotypes that are associated with, or are indicative of a vulnerability to developing major depressive disorder (MDD). Here we identify seven promising MDD-associated traits identified by magnetic resonance imaging (MRI) or positron emission tomography (PET). We evaluate whether these traits are state-independent, heritable endophenotypes, or state-dependent phenotypes that may be useful markers of treatment efficacy. In MDD, increased activity of the amygdala in response to negative stimuli appears to be a mood-congruent phenomenon, and is likely moderated by the serotonin transporter gene (SLC6A4) promoter polymorphism (5-HTTLPR). Hippocampal volume loss is characteristic of elderly or chronically-ill samples and may be impacted by the val66met brain-derived neurotrophic factor (BDNF) gene variant and the 5-HTTLPR SLC6A4 polymorphism. White matter pathology is salient in elderly MDD cohorts but is associated with cerebrovascular disease, and is unlikely to be a useful marker of a latent MDD diathesis. Increased blood flow or metabolism of the subgenual anterior cingulate cortex (sgACC), together with gray matter volume loss in this region, is a well-replicated finding in MDD. An attenuation of the usual pattern of fronto-limbic connectivity, particularly a decreased temporal correlation in amygdala-anterior cingulate cortex (ACC) activity, is another MDD-associated trait. Concerning neuroreceptor PET imaging, decreased 5-HT1A binding potential in the raphe, medial temporal lobe, and medial prefrontal cortex (mPFC) has been strongly associated with MDD, and may be impacted by a functional single nucleotide polymorphism in the promoter region of the 5-HT1A gene (HTR1A: –1019C/G; rs6295). Potentially indicative of inter-study variation in MDD etiology or mood state, both increased and decreased binding potential of the serotonin transporter has been reported. Challenges facing the field include the problem of phenotypic and etiological heterogeneity, technological limitations, the confounding effects of medication, and non-disease related inter-individual variation in brain morphology and function. Further advances are likely as epigenetic, copy-number variant, gene-gene interaction, and genome-wide association (GWA) approaches are brought to bear on imaging data. PMID:19358877

Differential Patterning of Genes Involved in Serotonin Metabolism and Transport in Extra-embryonic Tissues of the Mouse

PubMed Central

Wu, Hsiao-Huei; Choi, Sera; Levitt, Pat

2016-01-01

Introduction Serotonin (5-HT) is an important neuromodulator, but recently has been shown to be involved in neurodevelopment. Although previous studies have demonstrated that the placenta is a major source of forebrain 5-HT during early forebrain development, the processes of how 5-HT production, metabolism, and transport from placenta to fetus are regulated are unknown. As an initial step in determining the mechanisms involved, we investigated the expression patterns of genes critical for 5-HT system function in mouse extraembryonic tissues. Methods Mid- through late gestation expression of 5-HT system-related enzymes, Tph1, Ddc, Maoa, and 5-HT transporters, Sert/Slc6a4, Oct3/Slc22a3, Vmat2/Slc18a2, and 5-HT in placenta and yolk sac were examined, with cell type-specific resolution, using multiplex fluorescent in situ hybridization to co-localize transcripts and immunocytochemistry to co-localize the corresponding proteins and neurotransmitter. Results Tph1 and Ddc are found in the syncytiotrophoblast I (SynT-I) and sinusoidal trophoblast giant cells (S-TGC), whereas Maoa is expressed in SynT-I, syncytiotrophoblast II (SynT-II) and S-TGC. Oct3 expression is observed in the SynT-II only, while Vmat2 is mainly expressed in S-TGC. Surprisingly, there were comparatively high expression of Tph1, Ddc, and Maoa in the yolk sac visceral endoderm. Discussion In addition to trophoblast cells, visceral endoderm cells in the yolk sac may contribute to fetal 5-HT production. The findings raise the possibility of a more complex regulation of 5-HT access to the fetus through the differential roles of trophoblasts that surround maternal and fetal blood space and of yolk sac endoderm prior to normal degeneration. PMID:27238716

Optical and positron annihilation spectroscopic studies on PMMA polymer doped by rhodamine B/chloranilic acid charge transfer complex: Special relevance to the effect of γ-ray irradiation.

PubMed

Hassan, H E; Refat, Moamen S; Sharshar, T

2016-04-15

Polymeric sheets of poly (methylmethaclyerate) (PMMA) containing charge transfer (CT) complex of rhodamine B/chloranilic acid (Rho B/CHA) were synthesized in methanol solvent at room temperature. The systematic analysis done on the Rho B and its CT complex in the form of powder or polymeric sheets confirmed their structure and thermal stability. The IR spectra interpreted the charge transfer mode of interaction between the CHA central positions and the terminal carboxylic group. The polymer sheets were irradiated with 70 kGy of γ radiation using (60)Co source to study the enhanced changes in the structure and optical parameters. The microstructure changes of the PMMA sheets caused by γ-ray irradiation were analyzed using positron annihilation lifetime (PAL) and positron annihilation Doppler broadening (PADB) techniques. The positron life time components (τ(i)) and their corresponding intensities (I(i)) as well as PADB line-shape parameters (S and W) were found to be highly sensitive to the enhanced disorder occurred in the organic chains of the polymeric sheets due to γ-irradiation. Copyright © 2016 Elsevier B.V. All rights reserved.

On possible interpretations of the high energy electron–positron spectrum measured by the Fermi Large Area Telescope

DOE PAGES

Grasso, D.; Profumo, S.; Strong, A. W.; ...

2009-07-11

The Fermi-LAT experiment recently reported high precision measurements of the spectrum of cosmic-ray electrons-plus-positrons (CRE) between 20 GeV and 1 TeV. The spectrum shows no prominent spectral features, and is significantly harder than that inferred from several previous experiments. In this paper, we discuss several interpretations of the Fermi results based either on a single large scale Galactic CRE component or by invoking additional electron–positron primary sources, e.g. nearby pulsars or particle dark matter annihilation. We show that while the reported Fermi-LAT data alone can be interpreted in terms of a single component scenario, when combined with other complementary experimentalmore » results, specifically the CRE spectrum measured by H.E.S.S. and especially the positron fraction reported by PAMELA between 1 and 100 GeV, that class of models fails to provide a consistent interpretation. Rather, we find that several combinations of parameters, involving both the pulsar and dark matter scenarios, allow a consistent description of those results. Finally, we also briefly discuss the possibility of discriminating between the pulsar and dark matter interpretations by looking for a possible anisotropy in the CRE flux.« less

68. GENERAL VIEW OF SOUTH AND EAST SIDES OF SLC3W ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

68. GENERAL VIEW OF SOUTH AND EAST SIDES OF SLC-3W LIQUID OXYGEN APRON. CABLE TRAYS IN FOREGROUND - Vandenberg Air Force Base, Space Launch Complex 3, Launch Pad 3 West, Napa & Alden Roads, Lompoc, Santa Barbara County, CA

Polymorphisms at the 3' untranslated region of SLC11A1 gene are associated with protection to Brucella infection in goats.

PubMed

Iacoboni, Paola A; Hasenauer, Flavia C; Caffaro, M Eugenia; Gaido, Analia; Rossetto, Cristina; Neumann, Roberto D; Salatin, Antonio; Bertoni, Emiliano; Poli, Mario A; Rossetti, Carlos A

2014-08-15

Goats are susceptible to brucellosis and the detection of Brucella-infected animals is carried out by serological tests. In other ruminant species, polymorphisms in microsatellites (Ms) of 3' untranslated region (3'UTR) of the solute carrier family 11 member A1 (SLC11A1) gene were associated with resistance to Brucella abortus infection. Goats present two polymorphic Ms at the 3'UTR end of SLC11A1 gene, called regions A and B. Here, we evaluated if polymorphisms in regions A and/or B are associated with Brucella infection in goats. Serum (for the detection of Brucella-specific antibodies) and hair samples (for DNA isolation and structure analysis of the SLC11A1 gene) were randomly collected from 229 adult native goats from the northwest of Argentina. Serological status was evaluated by buffer plate antigen test (BPAT) complemented by the fluorescent polarization assay (FPA), and the genotype of the 3'UTR of the SLC11A1 gene was determined by capillary electrophoresis and confirmed by sequence analysis. Polymorphisms in regions A and B of the 3'UTR SLC11A1 gene were found statistically significant associated with protection to Brucella infection. Specifically, the association study indicates statistical significance of the allele A15 and B7/B7 genotype with absence of Brucella-specific antibodies (p=0.0003 and 0.0088, respectively). These data open a promising opportunity for limiting goat brucellosis through selective breeding of animals based on genetic markers associated with natural resistance to B. melitensis infection. Copyright © 2014 Elsevier B.V. All rights reserved.

Net Intestinal Transport of Oxalate Reflects Passive Absorption and SLC26A6-mediated Secretion

PubMed Central

Knauf, Felix; Ko, Narae; Jiang, Zhirong; Robertson, William G.; Van Itallie, Christina M.; Anderson, James M.

2011-01-01

Mice lacking the oxalate transporter SLC26A6 develop hyperoxalemia, hyperoxaluria, and calcium-oxalate stones as a result of a defect in intestinal oxalate secretion, but what accounts for the absorptive oxalate flux remains unknown. We measured transepithelial absorption of [14C]oxalate simultaneously with the flux of [3H]mannitol, a marker of the paracellular pathway, across intestine from wild-type and Slc26a6-null mice. We used the anion transport inhibitor DIDS to investigate other members of the SLC26 family that may mediate transcellular oxalate absorption. Absorptive flux of oxalate in duodenum was similar to mannitol, insensitive to DIDS, and nonsaturable, indicating that it is predominantly passive and paracellular. In contrast, in wild-type mice, secretory flux of oxalate in duodenum exceeded that of mannitol, was sensitive to DIDS, and saturable, indicating transcellular secretion of oxalate. In Slc26a6-null mice, secretory flux of oxalate was similar to mannitol, and no net flux of oxalate occurred. Absorptive fluxes of both oxalate and mannitol varied in parallel in different segments of small and large intestine. In epithelial cell lines, modulation of the charge selectivity of the claudin-based pore pathway did not affect oxalate permeability, but knockdown of the tight-junction protein ZO-1 enhanced permeability to oxalate and mannitol in parallel. Moreover, formation of soluble complexes with cations did not affect oxalate absorption. In conclusion, absorptive oxalate flux occurs through the paracellular “leak” pathway, and net absorption of dietary oxalate depends on the relative balance between absorption and SLC26A6-dependent transcellular secretion. PMID:22021714

Gene expression deficits in pontine locus coeruleus astrocytes in men with major depressive disorder.

PubMed

Chandley, Michelle J; Szebeni, Katalin; Szebeni, Attila; Crawford, Jessica; Stockmeier, Craig A; Turecki, Gustavo; Miguel-Hidalgo, Jose Javier; Ordway, Gregory A

2013-07-01

Norepinephrine and glutamate are among several neurotransmitters implicated in the neuropathology of major depressive disorder (MDD). Glia deficits have also been demonstrated in people with MDD, and glia are critical modulators of central glutamatergic transmission. We studied glia in men with MDD in the region of the brain (locus coeruleus; LC) where noradrenergic neuronal cell bodies reside and receive glutamatergic input. The expression of 3 glutamate-related genes (SLC1A3, SLC1A2, GLUL) concentrated in glia and a glia gene (GFAP) were measured in postmortem tissues from men with MDD and from paired psychiatrically healthy controls. Initial gene expression analysis of RNA isolated from homogenized tissue (n = 9-10 pairs) containing the LC were followed by detailed analysis of gene expressions in astrocytes and oligodendrocytes (n = 6-7 pairs) laser captured from the LC region. We assessed protein changes in GFAP using immunohistochemistry and immunoblotting (n = 7-14 pairs). Astrocytes, but not oligodendrocytes, demonstrated robust reductions in the expression of SLC1A3 and SLC1A2, whereas GLUL expression was unchanged. GFAP expression was lower in astrocytes, and we confirmed reduced GFAP protein in the LC using immunostaining methods. Reduced expression of protein products of SLC1A3 and SLC1A2 could not be confirmed because of insufficient amounts of LC tissue for these assays. Whether gene expression abnormalities were associated with only MDD and not with suicide could not be confirmed because most of the decedents who had MDD died by suicide. Major depressive disorder is associated with unhealthy astrocytes in the noradrenergic LC, characterized here by a reduction in astrocyte glutamate transporter expression. These findings suggest that increased glutamatergic activity in the LC occurs in men with MDD.

SLC7A11 expression is associated with seizures and predicts poor survival in patients with malignant glioma

PubMed Central

Robert, Stephanie M.; Buckingham, Susan C.; Campbell, Susan L.; Robel, Stefanie; Holt, Kenneth T.; Ogunrinu-Babarinde, Toyin; Warren, Paula Province; White, David M.; Reid, Meredith A.; Eschbacher, Jenny M.; Berens, Michael E.; Lahti, Adrienne C.; Nabors, Louis B.; Sontheimer, Harald

2015-01-01

Glioma is the most common malignant primary brain tumor. Their rapid growth is aided by tumor-mediated release of glutamate, creating peritumoral excitotoxic cell death and vacating space for tumor expansion. Glioma glutamate release may also be responsible for seizures, which complicate the clinical course for many patients and are often the presenting symptom. A hypothesized glutamate release pathway is the cystine/glutamate transporter System xc− (SXC), responsible for the cellular synthesis of glutathione. However, the relationship of SXC-mediated glutamate release, seizures, and tumor growth remains unclear. Probing expression of SLC7A11/xCT, the catalytic subunit of SXC, in patient tissue and tissues propagated in mice, we found that approximately 50% of patient tumors have elevated SLC7A11 expression. Compared with tumors lacking this transporter, in vivo propagated and intracranially implanted SLC7A11-expressing tumors grew faster, produced pronounced peritumoral glutamate excitotoxicity, induced seizures, and shortened overall survival. In agreement with animal data, increased SLC7A11 expression predicted shorter patient survival according to annotated genomic data in the REMBRANDT database. In a clinical pilot study we used Magnetic Resonance Spectroscopy (MRS) to determine SXC-mediated glutamate release by measuring acute changes in glutamate after administration of the FDA-approved SXC inhibitor, sulfasalazine. In 9 glioma patients with biopsy-confirmed expression of SXC, we found that its expression positively correlates with glutamate release, which is acutely inhibited with oral sulfasalazine. These data suggest that SXC is the major pathway for glutamate release from gliomas and that SLC7A11 expression predicts accelerated growth and peritumoral seizures. PMID:26019222

From early stress to 12-month development in very preterm infants: Preliminary findings on epigenetic mechanisms and brain growth.

PubMed

Fumagalli, Monica; Provenzi, Livio; De Carli, Pietro; Dessimone, Francesca; Sirgiovanni, Ida; Giorda, Roberto; Cinnante, Claudia; Squarcina, Letizia; Pozzoli, Uberto; Triulzi, Fabio; Brambilla, Paolo; Borgatti, Renato; Mosca, Fabio; Montirosso, Rosario

2018-01-01

Very preterm (VPT) infants admitted to Neonatal Intensive Care Unit (NICU) are at risk for altered brain growth and less-than-optimal socio-emotional development. Recent research suggests that early NICU-related stress contributes to socio-emotional impairments in VPT infants at 3 months through epigenetic regulation (i.e., DNA methylation) of the serotonin transporter gene (SLC6A4). In the present longitudinal study we assessed: (a) the effects of NICU-related stress and SLC6A4 methylation variations from birth to discharge on brain development at term equivalent age (TEA); (b) the association between brain volume at TEA and socio-emotional development (i.e., Personal-Social scale of Griffith Mental Development Scales, GMDS) at 12 months corrected age (CA). Twenty-four infants had complete data at 12-month-age. SLC6A4 methylation was measured at a specific CpG previously associated with NICU-related stress and socio-emotional stress. Findings confirmed that higher NICU-related stress associated with greater increase of SLC6A4 methylation at NICU discharge. Moreover, higher SLC6A4 discharge methylation was associated with reduced anterior temporal lobe (ATL) volume at TEA, which in turn was significantly associated with less-than-optimal GMDS Personal-Social scale score at 12 months CA. The reduced ATL volume at TEA mediated the pathway linking stress-related increase in SLC6A4 methylation at NICU discharge and socio-emotional development at 12 months CA. These findings suggest that early adversity-related epigenetic changes might contribute to the long-lasting programming of socio-emotional development in VPT infants through epigenetic regulation and structural modifications of the developing brain.

Integrating glycomics and genomics uncovers SLC10A7 as essential factor for bone mineralization by regulating post-Golgi protein transport and glycosylation.

PubMed

Ashikov, Angel; Abu Bakar, Nurulamin; Wen, Xiao-Yan; Niemeijer, Marco; Rodrigues Pinto Osorio, Glentino; Brand-Arzamendi, Koroboshka; Hasadsri, Linda; Hansikova, Hana; Raymond, Kimiyo; Vicogne, Dorothée; Simon, Marleen E H; Pfundt, Rolph; Timal, Sharita; Beumers, Roel; Biot, Christophe; Smeets, Roel; Kersten, Marjan; Huijben, Karin; Linders, Peter T A; van den Bogaart, Geert; van Hijum, Sacha A F T; Rodenburg, Richard; van den Heuvel, Lambertus P; van Spronsen, Francjan; Honzik, Tomas; Foulquier, Francois; van Scherpenzeel, Monique; Lefeber, Dirk J

2018-06-05

Genomics methodologies have significantly improved elucidation of Mendelian disorders. The combination with high-throughput functional-omics technologies potentiates the identification and confirmation of causative genetic variants, especially in singleton families of recessive inheritance. In a cohort of 99 individuals with abnormal Golgi glycosylation, 47 of which being unsolved, glycomics profiling was performed of total plasma glycoproteins. Combination with whole-exome sequencing in 31 cases revealed a known genetic defect in 15 individuals. To identify additional genetic factors, hierarchical clustering of the plasma glycomics data was done, which indicated a subgroup of four patients that shared a unique glycomics signature of hybrid type N-glycans. In two siblings, compound heterozygous mutations were found in SLC10A7, a gene of unknown function in human. These included a missense mutation that disrupted transmembrane domain 4 and a mutation in a splice acceptor site resulting in skipping of exon 9. The two other individuals showed a complete loss of SLC10A7 mRNA. The patients' phenotype consisted of amelogenesis imperfecta, skeletal dysplasia, and decreased bone mineral density compatible with osteoporosis. The patients' phenotype was mirrored in SLC10A7 deficient zebrafish. Furthermore, alizarin red staining of calcium deposits in zebrafish morphants showed a strong reduction in bone mineralization. Cell biology studies in fibroblasts of affected individuals showed intracellular mislocalization of glycoproteins and a defect in post-Golgi transport of glycoproteins to the cell membrane. In contrast to yeast, human SLC10A7 localized to the Golgi.Our combined data indicate an important role for SLC10A7 in bone mineralization and transport of glycoproteins to the extracellular matrix.